The endolysosomal pathway in Parkinson’s disease by Dr Rebecca Perrett
P
arkinson’s disease (PD) is the second most common late-onset neurodegenerative disease, and is clinically characterized by muscle rigidity, tremor and bradykinesia (slow movement). This is mainly caused by the progressive loss of dopaminergic neurons within the substantia nigra brain region, although other brain areas are affected (for example the basal ganglia and cerebral cortex), leading to cognitive and behavioural impairments.
It is clear from the pathology that PD involves impaired protein degradation and/or excessive protein accumulation, as affected brains are characterized by the presence of Lewy bodies (LBs), intraneuronal inclusions comprised primarily of a small protein called α-synuclein (1). α-synuclein is abundant in the normal human brain, although point mutations and gene amplifications lead to PD (2). α-synuclein has ‘prion-like’ properties; it can be transmitted to neighbouring cells, initiating a PD-like pathological process (3). Excessive or defective α-synuclein, is often ubiquitinated within LBs to promote its degradation. However, instead of being degraded, it aggregates into fibrils, which are particularly toxic to dopaminergic neurons.
pathway, a multi-vesicular pathway involved in protein recycling and degradation (Figure 1). Within this pathway, protein cargo is transported to the early endosome where it can either be recycled back to the plasma membrane or trafficked to the lysosome for degradation. In the latter route, the early endosome matures to become a late endosome, which then fuses with a lysosome, a low pH organelle containing degradative enzymes. In PD, overexpressed or mutated α-synuclein disrupts the endolysosomal pathway by interfering with membrane fusion events. In addition, α-synuclein aggregates at low pH, which may explain its aggregation in late endosomes and lysosomes, causing cellular dysfunction (4).
α-synuclein’s function may provide some clues regarding the disease aetiology. It regulates membrane fusion events in the endolysosomal
A number of PD associated genetic mutations or polymorphisms also disrupt protein trafficking and degradation via the endolysosomal
Figure 1.The endolysosomal pathway and PD causing mutations. Protein cargo is transported to the early endosome, where it is either recycled back to the plasma membrane or targeted to the lysosome for degradation. A number of PD causing mutations (LRRK2,VPS35, GBA, ATP13A2, ATP6AP2 and DNAJC13/RME8) cluster within this pathway. In addition, overexpressed or mutated α-synuclein aggregates at multiple points and causes endolysosomal dysfunction. (10).
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