α‐Synuclein stimulation of monoamine oxidase‐B and legumain protease mediates the pathology of Parkinson's disease

Abstract

Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with abnormal dopamine metabolism by MAO-B (monoamine oxidase-B) and intracellular α-Synuclein (α-Syn) aggregates, called the Lewy body. However, the molecular relationship between α-Syn and MAO-B remains unclear. Here, we show that α-Syn directly binds to MAO-B and stimulates its enzymatic activity, which triggers AEP (asparagine endopeptidase; legumain) activation and subsequent α-Syn cleavage at N103, leading to dopaminergic neurodegeneration. Interestingly, the dopamine metabolite, DOPAL, strongly activates AEP, and the N103 fragment of α-Syn binds and activates MAO-B. Accordingly, overexpression of AEP in SNCA transgenic mice elicits α-Syn N103 cleavage and accelerates PD pathogenesis, and inhibition of MAO-B by Rasagiline diminishes α-Syn-mediated PD pathology and motor dysfunction. Moreover, virally mediated expression of α-Syn N103 induces PD pathogenesis in wild-type, but not MAO-B-null mice. Our findings thus support that AEP-mediated cleavage of α-Syn at N103 is required for the association and activation of MAO-B, mediating PD pathogenesis.

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.…”

“…Previous studies show that physiological concentrations of DOPAL trigger the formation of α-Syn oligomers and aggregates in both a cell-free system and in cell culture, and produce cytotoxicity in vitro and in vivo . We recently reported that DOPAL activates AEP in dopaminergic neurons and leads to α-synuclein N103 cleavage by AEP, resulting in its aggregation and dopaminergic neuronal degeneration in the SN (21). Thus, DOPAL-α-Syn interactions may underlie the selective vulnerability of DA neurons in Parkinson’s disease (35–39), and we suspected that a similar interaction might occur between DOPEGAL and Tau in AD.…”

“…Thus, AEP plays a critical role in regulating Aβ and Tau pathogenesis. Most recently, we reported that AEP is activated by 3,4-dihydroxyphenylacetaldehyde (DOPAL), a highly toxic and oxidative dopamine (DA) metabolite, in the substantia nigra (21). Active AEP subsequently cleaves α-synuclein at N103 and promotes its aggregation and dopameringeric neuronal loss, leading to motor dysfunction in animal models of Parkinson’s disease (PD) (22).…”

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

“…TUNEL and LDH analysis revealed that both MAO-A and MAO-B overexpression significantly activated AEP, increased Tau N368 cleavage, and magnified Tau neurotoxicity as measured by TUNEL, LDH, and loss of the catecholaminergic marker tyrosine hydroxylase (TH) (Supplemental Figure 3). By contrast, preventing DOPEGAL production by siRNA knockdown of DBH attenuated AEP activation and Tau-triggered cell we reported that AEP is activated by 3,4-dihydroxyphenylacetaldehyde (DOPAL), a highly toxic and oxidative dopamine (DA) metabolite, in the substantia nigra (21). Active AEP subsequently cleaves α-synuclein at N103 and promotes its aggregation and dopaminergic neuronal loss, leading to motor dysfunction in animal models of Parkinson's disease (PD) (22).…”

PINK1 Regulates Dopamine and Lipids at Mitochondria to Maintain Synapses and Neuronal Function

“…PINK1 specific modification of TH at the mitochondrial membrane or at MAMs provides addition burden to dopaminergic neurons and the PD gene product α-synuclein has previously been implicated in TH 17 regulation at mitochondrial-ER contact sites 88 . Parkin is known to suppress MAO 89 , a mitochondrial anchored enzyme responsible for dopamine degradation and mitochondrial DNA damage 90 and which is implicated in the pathogenesis of PD 91 .…”