The endosomal pathway in Parkinson's disease

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Highlights

  • Multiple genes that have been implicated in Parkinson's disease function in the endosomal-lysosomal pathway

  • The main disease causing protein, alpha-synuclein, is trafficked within endosomes

  • Neuromelanin deposition in dopaminergic neurons could lead to depletion of functional endolysosomes with increasing age

  • Ubiquitin signaling could provide the link between genetic and acquired defects in endosomal trafficking in Parkinson's disease

Abstract

Parkinson's disease is primarily a movement disorder with predilection for the nigral dopaminergic neurons and is often associated with widespread neurodegeneration and diffuse Lewy body deposition. Recent advances in molecular genetics and studies in model organisms have transformed our understanding of Parkinson's pathogenesis and suggested unifying biochemical pathways despite the clinical heterogeneity of the disease. In this review, we summarized the evidence that a number of Parkinson's associated genetic mutations or polymorphisms (LRRK2, VPS35, GBA, ATP13A2, ATP6AP2, DNAJC13/RME-8, RAB7L1, GAK) disrupt protein trafficking and degradation via the endosomal pathway and discussed how such defects could arise from or contribute to the accumulation and misfolding of α-synuclein in Lewy bodies. We propose that an age-related pathological depletion of functional endolysosomes due to neuromelanin deposition in dopaminergic neurons may increase their susceptibility to stochastic molecular defects in this pathway and we discuss how enzymes that regulate ubiquitin signaling, as exemplified by the ubiquitin ligase Nedd4, could provide the missing link between genetic and acquired defects in endosomal trafficking. This article is part of a Special Issue entitled 'Neuronal Protein'.

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.

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