TrkB neurotrophic activities are blocked by α-synuclein, triggering dopaminergic cell death in Parkinson’s disease

Abstract

BDNF/TrkB neurotrophic signaling is essential for dopaminergic neuronal survival, and the activities are reduced in the substantial nigra (SN) of Parkinson's disease (PD). However, whether α-Syn (alpha-synuclein) aggregation, a hallmark in the remaining SN neurons in PD, accounts for the neurotrophic inhibition remains elusive. Here we show that α-Syn selectively interacts with TrkB receptors and inhibits BDNF/TrkB signaling, leading to dopaminergic neuronal death. α-Syn binds to the kinase domain on TrkB, which is negatively regulated by BDNF or Fyn tyrosine kinase. Interestingly, α-Syn represses TrkB lipid raft distribution, decreases its internalization, and reduces its axonal trafficking. Moreover, α-Syn also reduces TrkB protein levels via up-regulation of TrkB ubiquitination. Remarkably, dopamine's metabolite 3,4-Dihydroxyphenylacetaldehyde (DOPAL) stimulates the interaction between α-Syn and TrkB. Accordingly, MAO-B inhibitor rasagiline disrupts α-Syn/TrkB complex and rescues TrkB neurotrophic signaling, preventing α-Syn-induced dopaminergic neuronal death and restoring motor functions. Hence, our findings demonstrate a noble pathological role of α-Syn in antagonizing neurotrophic signaling, providing a molecular mechanism that accounts for its neurotoxicity in PD.

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus

“…We observed the appearance of hyperphosphorylated, AEP-cleaved, and Gallyas-Braak-positive forms of Tau in the EC, HC, and Cx of both transgenic strains following intra-LC infusion of mCherry + Tau virus. Importantly, generating the neurotoxic DA metabolite DOPAL in PD (21,45), and here we show that NE metabolism into DOPEGAL by MAO-A in the progression of AD-like pathology. Combined, these results support our model that DA metabolism into DOPAL and MAO-A-mediated conversion of NE into DOPEGAL induce α-synuclein toxicity in SN and Tau toxicity in LC, respectively, leading to the selective vulnerability of catecholamine neurons in PD and AD (Figure 12).…”

The Norepinephrine Metabolite DOPEGAL Confers Locus Coeruleus Tau Vulnerability and Propagation via Asparagine Endopeptidase

“…For instance, DOPEGAL and MAO-A levels are elevated 2.8- and 3.6-fold in AD LC neuronal cell bodies compared to controls (24), while MAO-B expression and activity are higher in multiple brain regions and cell types in AD (41, 42). While both MAO-A and MAO-B were capable of increasing AEP activity, Tau N368 cleavage, and cell death in our experiments, we favor MAO-A as the main driver of DOPEGAL production in vivo , with MAO-B playing a greater role generating the neurotoxic DA metabolite DOPAL in PD (21, 43) (Figure 7); that said, confirming this hypothesis will require additional experiments.…”

BDNF as a Promising Therapeutic Agent in Parkinson’s Disease

“…Decreased BDNF concentration in serum and brain is accompanied by an increase in degeneration of dopaminergic neurons in PD, which leads to movement disorders, cognitive deficit, and mental disorders [63][64][65][66] and also correlates with memory impairment in AD [67,68]. There are data indicating that a decrease in BDNF levels in PD may contribute to overexpression of alpha-synuclein (ASN) and inhibition of dopamine (DA) synthesis [69][70][71]. Moreover, it was reported that ASN overexpression downregulated BDNF transcription and impaired BDNF trafficking in neurons [53].…”