α-Synuclein Mutation Inhibits Endocytosis at Mammalian Central Nerve Terminals

Abstract

␣-Synuclein (␣-syn) missense and multiplication mutations have been suggested to cause neurodegenerative diseases, including Parkinson's disease (PD) and dementia with Lewy bodies. Before causing the progressive neuronal loss, ␣-syn mutations impair exocytosis, which may contribute to eventual neurodegeneration. To understand how ␣-syn mutations impair exocytosis, we developed a mouse model that selectively expressed PD-related human ␣-syn A53T (h-␣-syn A53T ) mutation at the calyx of Held terminals, where release mechanisms can be dissected with a patch-clamping technique. With capacitance measurement of endocytosis, we reported that h-␣-syn A53T , either expressed transgenically or dialyzed in the short term in calyces, inhibited two of the most common forms of endocytosis, the slow and rapid vesicle endocytosis at mammalian central synapses. The expression of h-␣-syn A53T in calyces also inhibited vesicle replenishment to the readily releasable pool. These findings may help to understand how ␣-syn mutations impair neurotransmission before neurodegeneration.

Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS

“…Indeed, using a combination of FM1-43 dye loading and unloading experiments together with electrophysiology, we find that OE of TDP-43 WT or TDP-43 G298S in motor neurons leads to defects in SV endocytosis but not exocytosis. Although loss of endogenous fly TDP-43 (TBPH) has been shown to cause reduced expression of the synaptic proteins Syntaxin (Romano et al, 2014) and Cacophony (Chang et al, 2014) at the NMJ, and defects in SVC have been previously described in Parkinson’s disease (Xu et al, 2016), here we provide mechanistic insights into reduced SV endocytosis at the NMJ, in the context of TDP-43 toxicity.…”

α-Synuclein – Regulator of Exocytosis, Endocytosis, or Both?

“…When fast mechanisms fail, CME will probably still be capable of maintaining presynaptic homeostasis to a certain level, and this is what one might see as a slowing down of endocytosis/membrane retrieval [48,49], or bulk endocytosis may take over, as seen in lamprey synapses upon intense stimulation [50]. Although these studies clearly show a disruption of endocytosis, they do not point to any specific 'pathway' that a-synuclein is potentially involved in.…”

“…However, membrane retrieval was delayed in A53T a-synuclein-expressing calyces. Furthermore, acute short-term whole-cell dialysis of A53T as well as wild-type a-synuclein delayed membrane retrieval, indicating a direct interaction with, and influence on, membrane properties by a-synuclein [49].…”

“…Intriguingly, recent efforts now reveal that a-synuclein plays a role in the endocytosis of synaptic vesicle [48][49][50]. In mice with simultaneous knockout of a-, b-, and g-synuclein, synaptic vesicle exo-and endocytosis was monitored using a fluorescent sensor reporting on the recycling of synaptic vesicles.…”

“…Neurons with a high rate of exocytosis, such as the dopaminergic neurons of the substantia nigra with their continuous pacemaker activity [70], may rely on fast endocytosis, while other neurons are rely mainly on CME and are less affected when fast mechanisms of endocytosis are disturbed. The results of capacitance measurements show that a-synuclein is possibly directly involved in the step of membrane retrieval [49]. However, rather than speaking of fast and slow endocytosis, which makes sense when looking at the timescale, one might more appropriately classify the processes into endocytosis upon intense stimulation and endocytosis upon moderate stimulation.…”