Abstract
The midbrain dopaminergic neurons of the substantia nigra and the ventral tegmental area play vital roles in the regulation of voluntary movement, emotion and reward in humans. These neurons are highly metabolic and are under constant oxidative stress. The dopaminergic neurons form extensive synaptic projections to the striatum. When these neurons start dying or when their synaptic connections fail, humans develop Parkinson's disease. This disease is accompanied by the accumulation of toxic α-synuclein-containing protein aggregates in nigrostriatal processes. Synucleins accumulate in a majority of healthy nerve terminals in the central nervous system, but what causes the formation of pathological synuclein aggregates is unclear. Recent studies point out that the interface between membrane trafficking in the nerve terminal and the autophagy–lysosomal pathway is the site for the aggregate assembly. An urgent goal is to find therapeutic targets at early stages of the disease when neurons are still functional.
Highlights
Among the first neurodegenerative changes that occur in Parkinson’s disease (PD) in the brain is a loss of dopaminergic nerve terminals in the striatum, accompanied by the accumulation of α-synuclein-containing protein aggregates in nigrostriatal processes known as Lewy neuritis (Lotharius and Brundin, 2002; Braak et al, 2003; Hansen and Li, 2012)
Recent genetic rescue experiments in mice with a PD-related mutation R258Q in synaptojanin1 did not report any accumulation of protein aggregates at synapses but observed abnormal accumulation of membrane vesicles and folds in mDA, suggesting that other defects in membrane trafficking may underlay early PD pathology (Boassa et al, 2013; Cao et al, 2017)
Several recent studies linked endophilin and its endocytic binding partner synaptojanin to the maturation of autophagosomes in the synapse (Murdoch et al, 2016; Soukup et al, 2016; Soukup and Verstreken, 2017), which expanded its role far beyond the synaptic vesicle (SV) recycling and synaptic compartment, and allowed linking it to pathological neurodegenerative conditions, including PD, in accordance with the complex phenotype of the endophilin triple knockout (TKO) (Fig. 1)
Summary
Among the first neurodegenerative changes that occur in PD in the brain is a loss of dopaminergic nerve terminals in the striatum, accompanied by the accumulation of α-synuclein-containing protein aggregates in nigrostriatal processes known as Lewy neuritis (Lotharius and Brundin, 2002; Braak et al, 2003; Hansen and Li, 2012). Consistent with the membrane-associated function of synucleins in nerve terminals, transgenic mice overexpressing human α-synuclein displayed alterations of the internal synaptic membrane morphology (Boassa et al, 2013).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
