Synaptopathy: presynaptic convergence in frontotemporal dementia and amyotrophic lateral sclerosis

Abstract

Frontotemporal dementia and amyotrophic lateral sclerosis are common forms of neurodegenerative disease that share overlapping genetics and pathologies. Crucially, no significantly disease-modifying treatments are available for either disease. Identifying the earliest changes that initiate neuronal dysfunction is important for designing effective intervention therapeutics. The genes mutated in genetic forms of frontotemporal dementia and amyotrophic lateral sclerosis have diverse cellular functions, and multiple disease mechanisms have been proposed for both. Identification of a convergent disease mechanism in frontotemporal dementia and amyotrophic lateral sclerosis would focus research for a targetable pathway, which could potentially effectively treat all forms of frontotemporal dementia and amyotrophic lateral sclerosis (both familial and sporadic). Synaptopathies are diseases resulting from physiological dysfunction of synapses, and define the earliest stages in multiple neuronal diseases, with synapse loss a key feature in dementia. At the presynapse, the process of synaptic vesicle recruitment, fusion and recycling is necessary for activity-dependent neurotransmitter release. The unique distal location of the presynaptic terminal means the tight spatio-temporal control of presynaptic homeostasis is dependent on efficient local protein translation and degradation. Recently, numerous publications have shown that mutations associated with frontotemporal dementia and amyotrophic lateral sclerosis present with synaptopathy characterized by presynaptic dysfunction. This review will describe the complex local signalling and membrane trafficking events that occur at the presynapse to facilitate neurotransmission and will summarize recent publications linking frontotemporal dementia/amyotrophic lateral sclerosis genetic mutations to presynaptic function. This evidence indicates that presynaptic synaptopathy is an early and convergent event in frontotemporal dementia and amyotrophic lateral sclerosis and illustrates the need for further research in this area, to identify potential therapeutic targets with the ability to impact this convergent pathomechanism.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; presynaptic; synaptic dysfunction; synaptic vesicle; synaptopathy.

Figure 1

Major known genes causative for ALS and FTD associated with synaptic dysfunction. The genetics of the two neurodegenerative disorders overlap significantly, with many genes found to be implicated in the pathology of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Emerging evidence suggests that misregulation of these genes contribute to synaptic dysfunction and loss in disease. The function of each of the encoded proteins is also shown. Created with BioRender.com.

Figure 2

Synaptic vesicle trafficking in the pre-synaptic terminal. Schematic representation showing synaptic vesicle exocytosis, endocytosis and recycling. Synaptic vesicles from the recycling pool undergo docking at the presynaptic active zone to form the readily releasable pool (RRP). The docked synaptic vesicles are primed for fusion through interactions between synaptobrevin-2 (VAMP2) and the plasma membrane proteins SNAP-25 and syntaxin-1 (STX1) to form the SNARE complex. Munc-18 and Munc-13 also support the complex assembly. Super priming results from the association of the calcium-binding protein, synaptotagmin-1 (SYT1), and complexin (CPX) with the SNARE proteins to stabilize the complex further. An arriving action potential then triggers the entry of Ca²⁺ via voltage-gated channels. Ca²⁺ binds to SYT1, leading to vesicle fusion with the membrane and neurotransmitter release. Vesicles are retrieved from the plasma membrane via clathrin-mediated endocytosis (CME), ultrafast endocytosis (UFE) or activity-dependent bulk endocytosis (ADBE). The latter two pathways generate endosomes directly from the plasma membrane, with CME initiated at this site, but completing on these presynaptic endosomes. Synaptic vesicles are reformed by clathrin coats budding from endosomes or vesicular carriers selectively trafficked via the endolysosomal system for degradation. Created with BioRender.com.

Figure 3

Molecular mechanisms underlying presynaptic dysfunction in ALS and FTD pathogenesis. Schematic representation of the presynaptic terminal showing the roles of amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD)-associated genes in the synaptic vesicle cycle and the pathways that are dysregulated. Synaptopathy in ALS and FTD may be caused by misregulation of presynaptic vesicle pools, alterations to exocytosis and endocytosis, and dysregulation of the endolysosomal system, leading to disrupted synaptic activity and neuronal function. Created with BioRender.com.