
==== Front
J Biol Chem
J Biol Chem
The Journal of Biological Chemistry
0021-9258
1083-351X
American Society for Biochemistry and Molecular Biology

S0021-9258(24)02104-5
10.1016/j.jbc.2024.107603
107603
JBC Reviews
Unveiling defects of secretion mechanisms in Parkinson’s disease
Filippini Francesca 12
Galli Thierry thierry.galli@inserm.fr
34∗
1 Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA
2 Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut, USA
3 Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris, INSERM U1266, Membrane Traffic in Healthy & Diseased Brain, Paris, France
4 Groupe Hospitalier Universitaire Paris Psychiatrie & Neurosciences, Paris, France
∗ For correspondence: Thierry Galli thierry.galli@inserm.fr
25 7 2024
9 2024
25 7 2024
300 9 10760330 1 2024
11 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Neurodegenerative diseases are characterized by progressive dysfunction and loss of specific sets of neurons. While extensive research has focused on elucidating the genetic and epigenetic factors and molecular mechanisms underlying these disorders, emerging evidence highlights the critical role of secretion in the pathogenesis, possibly even onset, and progression of neurodegenerative diseases, suggesting the occurrence of non-cell-autonomous mechanisms. Secretion is a fundamental process that regulates intercellular communication, supports cellular homeostasis, and orchestrates various physiological functions in the body. Defective secretion can impair the release of neurotransmitters and other signaling molecules, disrupting synaptic transmission and compromising neuronal survival. It can also contribute to the accumulation, misfolding, and aggregation of disease-associated proteins, leading to neurotoxicity and neuronal dysfunction. In this review, we discuss the implications of defective secretion in the context of Parkinson’s disease, emphasizing its role in protein aggregation, synaptic dysfunction, extracellular vesicle secretion, and neuroinflammation. We propose a multiple-hit model whereby protein accumulation and secretory defects must be combined for the onset and progression of the disease.

Keywords

protein secretion
Parkinson’s disease
synapse
extracellular vesicles
microglia
astrocytes
Abbreviations

CNS central nervous system

DLB dementia with Lewy body syndrome

LRRK2 Leucin-rich repeat kinase 2

MVBs multivesicular bodies

PD Parkinson's disease

VPS35 vacuolar protein sorting 35

Reviewed by members of the JBC Editorial Board. Edited by Phillip A. Cole
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pmcNeurodegenerative diseases are a group of heterogeneous disorders characterized by the progressive degeneration of the structure and function of neurons in the central nervous system (CNS) and peripheral nervous system. Among those, Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) feature the progressive loss of specific neuronal populations in the brain, which are involved in motor and cognitive functions. These conditions share common underlying principles yet exhibit distinct clinical features and affected brain regions. So far, no curative treatments have been discovered, only symptomatic ones, thus leading to increased interest in further investigation of the underlying pathogenic mechanisms. A main reason for the lack of proper efficient therapies might reside in the poor knowledge of early mechanisms of neurodegenerative diseases and their pre-symptomatic signs.

In this review, we will focus on secretion and PD, conscious that molecular mechanisms and impaired cellular processes are shared among different neurodegenerative disorders listed above.

Several studies have established the importance of the endolysosomal system in the context of neurodegeneration (1). Intense membrane trafficking occurs into and out of the endolysosomal system, highly tuned to control the modification and secretion of newly synthesized cargoes, as well as the degradation of internalized and intracellular elements. Secretion, or exocytosis, is the last step in this process, allowing for the release of vesicular content into the extracellular space by fusing secretory vesicles with the plasma membrane. It is now clear that defects in multiple steps of this pathway are a common feature of both genetic and sporadic forms (2).

Cells secrete a diverse array of molecules, including proteins, peptides, hormones, neurotransmitters, growth factors, cytokines, and lipids. Since the work of George Palade (3), the so-called conventional secretion has been seen as a route from the endoplasmic reticulum to the Golgi apparatus to the cell surface, involving several steps of vesicle budding, translocation, and fusion (4). As part of the intracellular membrane trafficking system, endolysosomes constitute an essential element at the crossroads of anabolism and catabolism. Seminal work by Alex Novikoff and Christian de Duve set the basic principles of late endosomes/multivesicular bodies (MVBs) and lysosomal structure and function, particularly their role in degradative mechanisms. In addition to this well-established role, Alex Novikoff even anticipated that MVBs “may be one of the routes important for the turnover of cell surface macromolecules” (5), hypothesizing in the release of extracellular vesicles generated in late endosomes/MVBs and the concept of endolysosomal secretion, as part of so-called unconventional secretion. Defects in both conventional and unconventional secretion could impair the release of essential signaling molecules, compromising cell communication and survival leading to a broad spectrum of pathologies. Given the importance of secretion in many different cellular processes, it is no surprise that there has been increasing effort in recent years to understand the mechanisms of cellular secretion in the context of human pathologies.

Parkinson’s disease was first described by James Parkinson in 1817 after observing patients with involuntary tremulous motion with lessened muscular power (6). Parkinson’s disease is a major progressive neurodegenerative disorder, with approximately 10 million affected people worldwide (7). The prevalence increases exponentially with age reaching the peak after 80 years of age (8) and it is estimated that about 1% of the population above 60 years old is affected by PD (9). The main neuropathological features of PD are α-synuclein-dense Lewy bodies and progressive loss of dopaminergic neurons (DA) in the substantia nigra pars compacta and their projection in the striatum. Early stages of PD are characterized by non-motor symptoms: sleep disorders, depression, loss of smell, and constipation, which are not well explained by a simple dopaminergic dysfunction (10). Later, motor symptoms include muscular rigidity, rest tremor, and postural and gait impairment (8) once 60 to 80% of the dopaminergic neurons have been irreversibly lost.

PD shares clinical features with dementia with Lewy body syndrome (DLB), with the major distinguishing detail being the timing of dementia: at least 1 year after the appearance of motor symptoms in PD whereas earlier cognitive impairment is associated with DLB (11). Whether PD and DLB are different phenotypes of the same underlying molecular and cellular pathogenic process remains an open question.

To date, ∼15% of PD cases have been found with inheritance patterns, showing significant variations in different populations (12). Consistent with a highly variable range of symptoms, multiple genes have been associated with PD: among others, SNCA, parkin, PINK1, DJ-1, LRRK2, GBA and VPS35. Interestingly, these genes encode proteins with connections to intracellular membrane trafficking. The more we know about the function of the proteins encoded by these genes, the more it appears that defects of intracellular membrane dynamics might be a central mechanism in, at least, the onset or early phases of the disease. Whether it would be a direct consequence of mutations in these genes, or more indirect mechanisms, studies have shown a role in secretion for several genes involved in PD. By focusing on different cellular processes that impact secretion, we aim to describe one aspect of the complicated PD pathophysiology, which cannot be summarized by dopaminergic neuron degeneration only. In this review, we particularly concentrate on the connections between α-synuclein and LRRK2 and secretion.

PD-associated genes and synaptic secretion

SNCA encodes for α-synuclein, a small acidic protein abundantly expressed in neurons of the CNS and PNS. Genetic studies have associated SNCA to both sporadic and genetic forms (13). The role of α-synuclein in PD was first described over 20 years ago in both idiopathic and genetic forms (14). As previously mentioned, accumulation, aggregation, and amyloid fibril formation of α-synuclein are considered a hallmark of the disease (Fig. 1), and there is an unsolved question of whether those are causative or a byproduct of the disease itself (15). Nevertheless, it appears that α-synuclein is involved in various cellular processes, resulting in its defective secretion, aggregation, and transmission which are all characteristics associated with the pathophysiology of PD (16) (Fig. 1). α-synuclein is a soluble cytosolic protein. Even though it lacks a secretory signal peptide sequence, it is found in extracellular compartments such as the CSF, saliva, plasma, and urine in healthy controls and patients with PD (17) suggesting that it could be secreted.Figure 1 Roles of α-synuclein in healthy and pathological conditions at the presynaptic terminal. α-synuclein exists as a monomer as well as an oligomer and it can form pathogenic fibrils and Lewy bodies (left). α-synuclein appears to play multiple functions at several steps of synaptic vesicle trafficking impacting the different pools of synaptic vesicles (reserve, readily releasable, recycling) (α-syn in blue), as well as the interaction with synaptic SNAREs all potentially impacting neurotransmitter release. Misfolding and aggregation of α-synuclein results in impaired neurotransmitter release, vesicle recycling and trafficking at the synaptic button and between synaptic buttons as well as destabilizing the SNARE complex assembly stability (α-syn in red). Aggregation of α-synuclein results in the accumulation of Lewy bodies in the intracellular space. DJ-1 also regulates synaptic vesicle endocytosis as DJ1 deficiency (DJ1 in red) impairs synaptic vesicle endocytosis and availability at nerve terminals.

α-synuclein is highly enriched in presynaptic nerve terminals and plays a key role in neurotransmission (18). It modulates the mobility of synaptic vesicles between presynaptic buttons, allowing to keep the recycling pool of synaptic vesicles readily available within the synapse (19). It is organized as a monomer but also as multimers resulting in synaptic vesicle clustering (20). Recent work showed that phosphorylation on S129 of α-synuclein disrupted synaptic vesicle trafficking in an activity-dependent manner (21), further highlighting the role of α-synuclein in secretion. The SNARE family of proteins (Soluble NSF Attachment REceptor) has been linked to α-synuclein modulation, affecting neurotransmitter release and contributing to neurodegeneration. SNAREs mediate membrane fusion by bringing two membranes into close apposition (>10 nm) allowing for fusion (22). SNAREs play a key role in the synaptic vesicle fusion at synapses, where the SNARE complex consists of the vesicular (v)-SNARE VAMP2 -, and the target (t)-SNAREs syntaxin-1A and SNAP25 at the presynaptic plasma membrane. Even though it remains unclear how α-synuclein is trafficked to the presynaptic terminal, studies have shown it interacts with synaptic vesicle membranes (23) and localizes mainly to the presynaptic terminal (24). α-synuclein was shown to directly interact with VAMP2 to promote SNARE-complex assembly in the presynaptic nerve and efficient neurotransmitter release (25) (Fig. 1). Moreover, the presynaptic protein Cysteine String Protein (CSPα) was shown to be in a complex with Heat shock cognate 70 kDa protein (Hsc70) and small glutamine-rich tetratricopeptide repeat protein (SGT) and this complex interacts with SNAP25, promoting SNARE-complex formation (26). Knocking out CSPα in mice results in fulminant neurodegeneration, rescued by α-synuclein and SNAP25 overexpression (27).

In another neurodegeneration mouse model, CSPα degradation and α-synuclein aggregation led to inhibition of SNARE-complex assembly with a slower rate of synaptic vesicle recycling (28). From these studies and others not described here, the connection between α-synuclein and synaptic SNAREs appears strong. However, how this leads to the neurodegeneration of subpopulations of neurons remains not fully understood.

Given the association between α-synuclein and PD, several studies have focused on dopamine release. For instance, mice lacking α-synuclein exhibit reduced dopamine striatal content and impaired motor response (29). Transgenic mouse line expressing truncated human α-synuclein develops aggregates, displays striatal dopamine deficiency and reduced locomotion, as well as synaptic accumulation of α-synuclein, accompanied by an age-dependent redistribution of the synaptic SNARE proteins SNAP25, syntaxin-1 and VAMP2, and reduction in dopamine release (30). Therefore, the regulation of SNAREs and secretion by α-synuclein might be prevalent in dopaminergic neurons.

Another gene involved in PD with presynaptic functions is DJ-1, encoded by PARK7 gene, with autosomal recessive inheritance in PD patients. DJ-1 mutation carriers display a significant level of non-motor symptoms when compared to other autosomal recessive forms of PD, placing DJ-1 in various important features of the symptom spectrum, including anxiety, cognition, and psychosis (10). Interestingly, DJ-1 deficiency impairs synaptic vesicle endocytosis and availability at nerve terminals (31) further suggesting presynaptic defects in PD.

In conclusion, the aggregation of α-synuclein in PD could induce a loss of function, impairing neurotransmission. Alternatively, impairment of expression of synaptic SNAREs which bind α-synuclein could cause α-synuclein aggregation, which would then appear rather as a mark of the onset of the disease. In both cases, it is relatively easy to consider that synaptic secretion defects might be a first hit in the onset of PD, leading to relatively minor prodromic cognitive symptoms that might often come undetected.

PD-associated genes and extracellular vesicle secretion

Extracellular vesicles (EVs) are a diverse group of membrane-bound nanovesicles that play a key role in cell-to-cell communication, immune response modulation, removal of intracellular elements, and participation in various physiological and pathological processes (32). EV release is observed in all cells, CNS resident cells included. In the brain, they are proposed to participate in synaptic communication, neurite growth, and neuronal survival (33).

Exosomes are a type of extracellular vesicles of ∼30 to 100 nm in diameter, generated as intraluminal vesicles in late endosomes/MVBs and secreted in normal and pathological conditions. Long regarded as cellular debris, exosomes have recently gained interest due to their discovered role in mediating intercellular communication. They deliver proteins, lipids, mRNA, and miRNA released by cells in the extracellular space (32). For the most part, their biogenesis requires the inward budding in MVBs, which allows the formation of intraluminal vesicles (ILVs) that are then secreted following the fusion of MVBs with the plasma membrane as exosomes (34). Exosome secretion is a ubiquitous and conserved cellular process including in the central nervous system performed by neurons, microglia, and astrocytes with even a proposed role as a neurotransmitter (35). Exosomes are important for physiological functions in cargo delivery in the extracellular space, but they are involved in the pathogenesis of several disorders, including neurodegenerative diseases like PD (36).

α-synuclein is a cytosolic protein deprived of a leader sequence for insertion in the ER, thus its secretion most likely occurs following its encapsulation in ILVs but, it could also cross the membrane of endosomes via an as-yet-unknown mechanism. Interestingly, α-synuclein was shown to be secreted by EVs in a Ca2+-dependent manner in SH-SY5Y cells (37). In the same cell lines, overexpression of α-synuclein resulted in its release into EVs which can be measured in the cell media (38). Furthermore, an important connection between lysosomal and autophagic dysfunctions and increased exosome-mediated secretion of α-synuclein was suggested. Indeed, inhibition of Atg5 which results in inhibition of autophagosome formation increased exosomal α-synuclein secretion, and the inhibition of the latter induced cell death (39). Pathogenic mutant A53T α-synuclein aggregates were shown to be released by endolysosomes in a VAMP7 and SNAP23-dependent manner in cultured neurons but, surprisingly, they did not appear to be associated with exosomes (40). Therefore, how α-synuclein monomers, multimers, and aggregates reach the luminal domain of endolysosomes might be a point of vulnerability in PD, leading to the accumulation and secretion of free and/or exosome-encapsulated pathogenic forms of the protein.

Nevertheless, a recent study showed that cerebrospinal fluid (CSF)-derived extracellular vesicles from PD patients induce α-synuclein propagation in vivo leading to PD-like symptoms in mice (41).

A recent study hypothesized the importance of lysosomal enzyme glucocerebrosidase (gene GBA, protein GCase) in EV secretion. 5 to 15% of PD patients carry a GBA mutation, making mutations in this gene the most common risk factor for PD (42). Several studies have reported that GBA mutation carriers display severe symptoms, such as visual hallucination or psychosis, earlier age onset, and faster progression of motor and cognitive symptoms (43). GBA regulates the homeostasis of glycosphingolipids by acting in the catabolism of glucosylceramide and glucosyl sphingosine. PD patients-derived fibroblasts with GBA-PD-related mutations were used to isolate and purify EVs. They observed that impaired GCase activity promotes EV release and that PD-GBA severe mutation increased the intracellular phosphorylation of α-synuclein. Papadopoulos and colleagues used in vitro and in vivo experiments to show that GCase overexpression significantly decreased exosome secretion and its inhibition in transgenic mice significantly increased intracellular α-synuclein oligomers (44).

Leucin-rich repeat kinase 2 (LRRK2), has been intensively studied in the context of PD (45). Familial PD-LRRK2 missense autosomal dominant mutations result in increased kinase activity. Various signaling pathways activate and recruit LRRK2 to distinct compartments in the cell, such as the lysosome where it promotes restoration of lysosome integrity (46). LRRK2 was further found in exosomes isolated from the CSF and urine (47). Overexpressing a kinase hyperactive mutation of LRRK2 resulted in an abnormal accumulation of MVBs (48). With caution in the interpretation of overexpressing studies performed in cells, this result was confirmed by a study performed on macaques, where two different brain-penetrant LRRK2 inhibitors (PFE-360 and MLi2) were included in the diet and led to reduced exosome-LRRK2 protein and pRab10 - a known substrate of LRRK2 phosphorylation activity - in urine as well as reduced LRRK2 autophosphorylation in CSF (49). Additionally, these results were further validated in rodents, where urinary EVs showed increased levels of LRRK2 autophosphorylation in individuals carrying the kinase-hyperactive G2019S mutation (50).

The search of PD biomarkers has recently shown that the secreted peptide VGF (non-acronymic, unrelated to VEGF)/secretogranin (SG) VII, was decreased in CSF, blood, and urine of PD patients (51, 52, 53, 54). VGF appears as a soluble protein packed into large dense core vesicles (55) specifically expressed in neurons and some neuroendocrine cells. It was originally identified as a nerve growth factor target gene (56) whose proteolytical products are bioactive peptides enriched in secretory vesicles mainly after cell depolarization (57). These peptides regulate a variety of roles including energy homeostasis and behavior, anxiety, learning, and memory (58). Our group recently found evidence for the secretion of the pro-peptide form of VGF and showed that this was LRRK2-dependent, via the interaction between LRRK2 and the two v-SNAREs VAMP4 and VAMP7 (59). VAMP4 plays a role at the interface between the Golgi apparatus and endosomes which is regulated by LRRK2 (60). Interestingly, pro-VGF was largely found associated with extracellular vesicles which are released in a VAMP7-dependent manner (Fig. 2). Therefore VGF, in addition to being a PD biomarker, might contribute to the onset and/or progression of PD. Impaired processing of the pro-peptide and/or its secretion could play a role in the early cognitive defects of PD. How VGF finds its way and from where (brain, peripheral tissues) into body fluids including urine so that it is decreased in Parkinson’s patients remains an issue to be fully addressed in vivo (Fig. 2).Figure 2 Roles of LRRK2 in intracellular trafficking and secretion.A, structural domains of LRRK2, with Roc-COR and kinase domain constituting the enzymatic core of the protein. B, LRRK2 plays several roles in different intracellular membrane compartments. These functions could be mediated by its kinase activity phosphorylating Rab proteins, and its binding of the vesicular SNAREs VAMP4 and VAMP7, all key regulators of post-Golgi membrane trafficking. Once phosphorylated, Rab proteins lose their ability to bind their effectors as they become trapped on membrane surfaces. PD-related mutations result in hyperphosphorylated LRRK2 which acts particularly at numerous steps of the endolysosomal system, such as early endosomes, MVBs, and lysosomes resulting in impaired post-Golgi trafficking. C, VAMP4 and VAMP7 bind LRRK2 and play a key role in trafficking between endosomes and the Golgi apparatus (VAMP4) and traffic to late endosomes and late endosomal secretion (VAMP7). The VGF neuropeptide is processed in several active peptides in the VAMP2-dependent conventional secretion, and this processing was found to depend on VAMP4. VPS35 is involved in endosome to Golgi apparatus transport and mutations enhance the secretion of lysosomal enzyme Cathepsin D. The pro-VGF was found to be released in a VAMP7-dependent manner by MVBs, an unconventional secretion. LRRK2 mutants were shown to retain VGF in the Golgi apparatus. α-synuclein monomers and aggregates were also shown to be released by MVBs. These later mechanisms might connect LRRK2 and α-synuclein roles in PD.

The vacuolar protein sorting 35 (VPS35), encoding for a fundamental component of the retromer complex, is also involved in recycling cargoes from endosomes to the trans-Golgi network or the plasma membrane. The precise role of retromer functions is partially known, but the ubiquitous expression suggests a role in membrane trafficking machinery in the CNS and peripheral tissues as well (61). PD-VPS35-mutation carriers display autosomal dominant inheritance and, so far, only the D620N mutation has been linked to PD (62). Studies on VPS35 also suggested a role in secretion, albeit not specifically related to EVs or exosomes because the D620N knock-in mouse results in impaired dopamine release (63). These mice also die prematurely and display significant neurodegeneration. Interestingly, in both overexpression studies and PD patients' fibroblasts, Vps35 D620N protein decreased the processing of endolysosomal enzyme Cathepsin D, promoting Cathepsin D secretion in the extracellular space (64). Interestingly, Vps35 D620N knock-in mice display a LRRK2-dependent increase in Rab10 phosphorylation compared to WT animals (65).

In conclusion, the involvement of extracellular vesicles underscores their pivotal role in the pathogenesis and progression of PD. How exosomes and possibly more generally EVs contribute to the pathology could rely on their ability to detoxify the intracellular environment and spread pathogenic proteins such as α-synuclein aggregates. It could also be related to a broader function of EVs in intercellular signaling based on their content in certain proteins (VGF?), lipids, and nucleic acids. Understanding how dopaminergic neurons might be more sensitive to the loss or increased presence of certain EVs in their environment remains a topic for further investigation. The complex contribution of the endolysosomal system could function to amplify the accumulation of defective protein aggregates. In a multiple-hit model of the disease, this might still not be sufficient to trigger the death of the DA neurons, but it might contribute to the spreading of the disease.

PD-associated genes and inflammatory-related secretion

As mentioned above, the role of inflammation in the development of PD is supported by extensive literature. Microglia, the resident immune cells of the CNS, are involved not only in homeostatic functions but also in the surveillance of the environment and maintenance of neuronal networks through synapse pruning, which is important for brain development, learning, memory, and injury repair. Microglia activation was shown to appear at the early stages of PD pathology and degenerate with time especially in cortical areas, with a proposed feedback loop between progressive inflammatory response and progression of the neurodegeneration.

It has been well established that inflammation involves the secretion of cytokines, signaling molecules involved in immune response.

When microglia respond to inflammation, cytokines are produced and secreted, including tumor necrosis factor α (TNF α and interleukins, IL). Activated microglia release massive pro-inflammatory factors that often result in dopaminergic neurons (DA) loss in PD. Interestingly enough, microglial cells secrete neurotrophic and anti-inflammatory factors and act in the formation of dendritic spines by releasing the brain-derived neurotrophic factor, BDNF (66). Pro-inflammatory cytokines such as TNF-α, interleukin-1 beta and IL-6 were found to be increased in the nigrostriatal region of postmortem brains from patients with sporadic, as well as in the CSF. On the other hand, BDNF levels were found to decrease suggesting that microglia might be activated and promote a variety of signals (67).

A recent study reported that primary microglia treated with human α-synuclein preformed fibrils release exosomes containing α-synuclein that induce protein aggregation in the recipient neuron suggesting a direct involvement of microglial secretion in PD. Microglial proinflammatory cytokines treatment further increased protein aggregation mediated by exosome release. The authors confirmed the importance of exosome-mediated α-synuclein aggregation by injecting exosomes isolated from α-synuclein preformed fibrils into the mouse striatum, resulting in time-dependent neurodegeneration (68).

Several groups have identified a key role of LRRK2 in microglia homeostasis (69) and secretion. Stimulating rat primary microglia with TLR4 resulted in activated microglia and increased LRRK2 activity and expression, and treatments with kinase inhibitors decreased TNFα release (70).

In a recent study, neurons, and microglia derived from human iPSCs (induced Pluripotent Stem Cells) were used to demonstrate that kinase-hyperactive LRRK2 neurons are susceptible to IFN- γ signaling and LRRK2 acts as a microglia regulator involved in the immune metabolic reprogramming (71).

Upon inflammatory stimuli, astrocytes change morphology and become activated in PD (72). The PD genes DJ-1, α-synuclein, PINK1, and Parkin have been associated with astrocyte-specific responses, while LRRK2 and GBA are associated with the normal physiology of those cells (73). DJ-1 is involved in neuroprotection by sensing oxidative stress and neuroinflammation (74), but precise details of this mechanism remain elusive. PTEN-induced kinase 1 (PINK1), encoded by the PARK6 gene, is found mutated in PD patients with autosomal recessive inheritance. It localizes to mitochondria and acts as a serine/threonine kinase responsible for protecting against oxidative stress-induced apoptosis (75). Most of the PD-associated PINK1 mutations are found within the kinase domain, suggesting a key role of this domain in the physiological role of PINK1 (76). Parkin is encoded by the PARK2 gene whose mutations lead to autosomal recessive forms of PD. Mutations in parkin are also found in sporadic PD (77). Parkin is a ubiquitin E3 protein-ligase, mediating mono-ubiquitination and polyubiquitination. It has been reported that parkin mutations, which can vary from missense or small deletion to deletion of hundreds of thousands of nucleotides, all result in parkin loss-of-function (78). Both Parkin and Pink1 play essential roles in mitophagy, the main catabolic pathway responsible for the elimination of dysfunctional mitochondria (79). As a result of mutations in these genes, astrocytes are activated and secrete IL1-α, C1q, and TNF-α, similar to microglia (80). Astrocytes also seem to be implicated in protecting the brain's intracellular environment following the activation of the immune response, by surrounding the healthy tissue and preventing the spread of toxic molecules (81).

In close proximity to glial cells and neurons, the blood-brain barrier (BBB) handles CNS protection, regulation of blood flow, and control of neuronal homeostasis building the so-called neurovascular unit. Both hypoperfusion and BBB disruption are linked to neuronal loss in neurodegenerative diseases like PD, as activated microglia and astrocytes release proinflammatory cytokines, affecting BBB functions (82). Investigating the role of the neurovascular unit is crucial in the context of PD to understand the complex interplay between secretion and different cell types (Fig. 3).Figure 3 Activation of microglia and astrocytes and secretion in PD. PD-associated gene mutations result in hyperactivation of microglia and reactive astrocytes in the central nervous system with observed increased cytokine secretion. The brain-blood barrier, which acts as a protection from damage to the brain, is in a close interplay with microglia and astrocytes, as well as neurons. Reactive cells in the CNS result in the disruption of the BBB, a characteristic found in PD patients.

A first glance at a more complex role of the immune system, including in neurodegeneration, came in 2003 with the Braak hypothesis (83). The authors observed that α-synuclein aggregation was found first outside the CNS (in the gut or nasal epithelia) suggesting that peripheral immune cells might be first responders to misfolded α-synuclein. In their hypothesis, α-synuclein aberrant accumulation would spread through the vagus nerve and reach the CNS in a later stage of PD. Recent studies on animal models have further validated this hypothesis (84). Interestingly enough, patients who have been vagotomized show a decreased risk of developing PD (85). More recently it has been shown that bidirectional communication occurs between the intestine and the brain through nerve fibers of both sympathetic and parasympathetic systems, as well as the vagus nerve and the intestinal immune system (86). Those systems interact and influence each other in their functions and mechanisms. In PD, it is thought that when this bidirectional axis is disrupted, early gut disturbances appear, with increased vulnerability of DA. Studies using rat models injected with the neurotoxin 6-OHDA (6-Hydroxydopamine, a toxic oxidative metabolite of dopamine applied to generate experimental models of PD), revealed elevated inflammatory markers and oxidative stress in the colon as well as decreased dopamine receptor levels (87). It appears clear that the enteric nervous system and the immune system, closely influenced by gut microbiota, form a crucial point of research in the PD field.

How the gut microbiome might be involved in neurodegeneration in the brain was explored by Matheoud and colleagues (88) in the mouse. They reported the role of PINK1 and Parkin in suppressing mitochondrial antigen presentation (MitAP). In their absence, elevated levels of mitochondrial antigens are presented on MHC class I molecules via the formation of mitochondria-derived vesicles (MDVs) that allow the transport of mitochondrial cargo to endosomes. Interestingly, the transport and fusion of MDVs with endosomes were previously shown to depend on VAMP7 (89). This work suggests an important connection between mitochondrial dynamics, antigen presentation regulation by PINK1 and Parkin, and the potential involvement of autoimmune mechanisms in PD etiology.

In conclusion, the intricate interplay between inflammation and PD involves the activation of microglia and astrocytes as well as peripheral immune cells. Notably, microglia undergo dynamic changes in morphology and function, contributing to both neuroprotection and inflammation-mediated neurodegeneration. The release of intracellular elements such as those coming from mitochondria might trigger inflammation and autoimmunity which could affect dopaminergic neurons for reasons yet to be explored. It is thus tempting to think that inflammation and auto-immunity might come as second or third hit following a defect in neurotransmission and the accumulation of defective proteins and organelles and possible unconventional secretion of some of these elements particularly those originating from the mitochondria.

Concluding Remarks

In conclusion, with this review we have tried to describe the intricate landscape of PD, exploring the multifaceted roles of α-synuclein aggregation, regulation of neurotransmitter release, EV secretion, and inflammation-related secretion. The more we investigate PD, the more this disease appears complex and not limited to neuronal cell autonomous degeneration. The interplay between different cell types and cell processes reveals the complexity of this pathology. Indeed, understanding the dynamics of cell secretion mechanisms not only enhances our grasp of disease development and progression but also paves the way for innovative therapeutic avenues. Like in cancer’s microenvironment, the concept of a dopaminergic neuron microenvironment with astrocytes, microglial and immune cells releasing important factors for survival and/or death, might be key to understanding the onset and progression of the disease over a long time.

One could hypothesize that early events include synaptic vesicle and endolysosomal defects in neurons and non-neuronal cells that impact the environment of dopaminergic neurons. At the same time, inflammation and autoimmunity might constitute additional hits further modifying the neuronal microenvironment and eventually leading to an auto-immune response and cell death (Fig. 4). These multiple hits might coincide on dopaminergic neurons because of a specific vulnerability to this microenvironment leading to their death.Figure 4 Multiple hits of impaired secretion in PD. Parkinson’s disease is a complex neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons which leads to cognitive and motor impairments. Secretion is found impaired upon several PD-associated gene mutations. The onset and progression of PD could result from different hits impacting secretory mechanisms:(1) α-synuclein aggregations lead to inhibition of synaptic vesicle release by interacting with SNAREs. (2) α-synuclein, GBA, and LRRK2 are associated with impaired EVs and exosome release; the secretion of the secretogranin VGF, a potential biomarker of PD, could be involved in a second hit. (3) Microglia and astrocytes play a critical role in secretion-related mechanisms in PD, being found activated with increased cytokines secretion in PD-related genes; the peripheral immune system is involved in impaired secretion that contributes to CNS-peripheral inflammation. (4) Microglia-astrocytes and neurons are in an interplay with the brain blood barrier and endothelial cells constituting the neurovascular unit, which is disrupted in PD.

Supporting information

This article contains supporting information.

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

Supporting information

Supporting Information

Acknowledgments

We thank all members of the Galli team for their assistance and discussions. Work in our group was funded by grants from the 10.13039/501100001665 French National Research Agency (MetDePaDi ANR-16-CE16-0012 , GlioUPS ANR-23-CE16-0035-01 ), 10.13039/501100006364 Institut National du Cancer (PLBIO 2018-149 ), 10.13039/501100002915 Fondation pour la Recherche Médicale (FRM, Labellisation), 10.13039/501100004431 Fondation de France (grant #00096652 ), and 10.13039/501100007492 Fondation Bettencourt Schueller (Coup d’Elan) to T. G and FRM PhD fellowship to F. F.

Author contributions

T. G. and F. F. writing–review & editing, T. G. and F. F. writing–original draft, T. G. and F. F. visualization, T. G. supervision, T. G. and F. F. funding acquisition, T. G. and F. F. conceptualization.
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