The endosomal pathway in Parkinson's disease
Graphical abstract
Introduction
Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting 1% of people over the age of 60. Clinically it is characterized primarily by a movement disorder causing resting tremor, bradykinesia, rigidity, postural instability and diverse non-motor symptoms including dementia, which in community-based studies, was reported in up to 80% of patients with long disease duration (Hely et al., 2008) This latter finding indicates that PD is a diffuse neurodegenerative disorder. Similarly, detailed neuropathological studies have shown that one of the cardinal histological features, the intraneuronal inclusions called Lewy bodies (LB), are detected in numerous cortical areas and often correlate with the extent of cognitive decline (Schneider et al., 2012). Despite this diffuse evolution, the presentation to health services is commonly due to the loss of a critical number of dopaminergic neurons in the substantia nigra (Lees et al., 2009) whereas in the minority of patients, dementia may be the predominant or presenting feature (often termed PD dementia).
Recent advances in sequencing technologies have transformed our molecular understanding of Parkinson's disease and suggested unifying themes despite its clinical heterogeneity, largely due to emerging genetic–pathological correlations (Tofaris, 2012). A major challenge ahead is the validation of the molecular mechanism(s) by which these genes cause the aforementioned clinical and pathological characteristics and accumulation of α-synuclein in LB, which is a sine qua non feature of the commonest form of sporadic PD. In this respect, it is imperative to ask whether an integrated cellular pathway based on molecular genetics and studies in model organisms can explain the relatively selective neuronal vulnerability initially and the diffuse evolution of the disease eventually. In this review we summarized the evidence that protein trafficking via the endosomal pathway fulfills these criteria in Parkinson's disease pathogenesis and discussed novel therapeutic targets within these protein networks.
Section snippets
The endosomal pathway
Endosomal trafficking is essential for the maintenance of cellular homeostasis and thus organismal viability as evidenced by the lethal phenotype of critical enzymes that regulate its multiple functions (Zeigerer et al., 2012). Endosomes are a critical hub for the re-use or breakdown of membrane-bound proteins, trafficking of Golgi-associated proteins and the extracellular release of proteins in exosomes (Fig. 1). Neurons are heavily dependent on such processes to fulfill their specialized
Endosomal defects in Parkinson's pathogenesis
Given the complexity of endosomal fusion and delivery systems, it is not surprising that many of these steps have been implicated in neurodegenerative or neurodevelopmental diseases. However the discovery of both genetic mutations (e.g. α-synuclein, VPS35, LRRK2, DNAJC13/RME-8) in late-onset familial PD which is clinically similar to sporadic disease and polymorphisms in genome-wide studies (e.g. GAK, Rab7L1, Nalls et al., 2014), that disrupt endosomal trafficking, strongly supports the notion
α-Synuclein degradation by the endosomal pathway
Although α-synuclein is degraded by both proteasomes and lysosomes, the latter have emerged as the most relevant degradative pathway in PD pathogenesis (reviewed in Tofaris, 2012). α-Synuclein was found in association with endosomes (Hasegawa et al., 2011, Boassa et al., 2013) and lysosomes extracted from mouse brains (Mak et al., 2010). Endosomal α-synuclein can either be targeted for degradation by lysosomes or enter the recycling endosome and be released in a process involving Rab11a and
Concluding remarks
In this review we have highlighted recent advances suggesting a central role for endosomal processing in PD pathogenesis. Molecular genetics indicate that disease causing mutations cluster within this pathway (Fig. 1) and alter receptor recycling and/or α-synuclein degradation. In turn, α-synuclein accumulation in cell and animal models further exacerbates defective endosomal processing by impairing the machinery involved in the sorting or fusion of endosomes.
We propose that such a vicious
Acknowledgments
G.K.T. is supported by a Wellcome Trust Intermediate Clinical Fellowship, the Oxford Biomedical Research Centre and the EPSRC.
References (131)
- et al.
PRA isoforms are targeted to distinct membrane compartments
J. Biol. Chem.
(2001) - et al.
Roc, a Ras/GTPase domain in complex proteins
Biochim. Biophys. Acta
(2003) - et al.
Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration
Cell
(2005) - et al.
Alterations in lysosomal and proteasomal markers in Parkinson's disease: relationship to alpha-synuclein inclusions
Neurobiol. Dis.
(2009) - et al.
Enhanced ubiquitin-dependent degradation by Nedd4 protects against alpha-synuclein accumulation and toxicity in animal models of Parkinson's disease
Neurobiol. Dis.
(2014) - et al.
The Arp2/3 activator WASH controls the fission of endosomes through a large multiprotein complex
Dev. Cell
(2009) - et al.
Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson's disease
Prog. Neurobiol.
(2005) - et al.
A FAM21-containing WASH complex regulates retromer-dependent sorting
Dev. Cell
(2009) - et al.
Homeostatic regulation of AMPA receptor trafficking and degradation by light-controlled single-synaptic activation
Neuron
(2011) - et al.
The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes
Cell
(2012)