Synucleinopathy-associated pathogenesis in Parkinson's disease and the potential for brain-derived neurotrophic factor

Abstract

The lack of disease-modifying treatments for Parkinson's disease (PD) is in part due to an incomplete understanding of the disease's etiology. Alpha-synuclein (α-syn) has become a point of focus in PD due to its connection to both familial and idiopathic cases-specifically its localization to Lewy bodies (LBs), a pathological hallmark of PD. Within this review, we will present a comprehensive overview of the data linking synuclein-associated Lewy pathology with intracellular dysfunction. We first present the alterations in neuronal proteins and transcriptome associated with LBs in postmortem human PD tissue. We next compare these findings to those associated with LB-like inclusions initiated by in vitro exposure to α-syn preformed fibrils (PFFs) and highlight the profound and relatively unique reduction of brain-derived neurotrophic factor (BDNF) in this model. Finally, we discuss the multitude of ways in which BDNF offers the potential to exert disease-modifying effects on the basal ganglia. What remains unknown is the potential for BDNF to mitigate inclusion-associated dysfunction within the context of synucleinopathy. Collectively, this review reiterates the merit of using the PFF model as a tool to understand the physiological changes associated with LBs, while highlighting the neuroprotective potential of harnessing endogenous BDNF.

Fig. 1. Pathogenic mechanisms consistently associated with Lewy bodies across multiple approaches.

Both immunofluorescence and LCM of LB-containing nigral neurons reveal alterations in proteolysis markers^, as well as alterations in transport/cytoskeleton organization^,. Some whole SN tissue analysis and LCM studies of nigral DA neurons also have detected proteolysis and transport/cytoskeletal dysfunction^–,,. Mitochondrial dysfunction is quite frequently detected by both whole SN tissue analysis and LCM approaches^–,,, however the association specifically with LBs has not directly been established.