Abstract
Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs). Protein phosphatase 2A (PP2A) is the major MAP phosphatase; however, little is known about its regulation at microtubules. α4 binds the PP2A catalytic subunit (PP2Ac) and the microtubule-associated E3 ubiquitin ligase MID1, and through unknown mechanisms can both reduce and enhance PP2Ac stability. We show MID1-dependent monoubiquitination of α4 triggers calpain-mediated cleavage and switches α4's activity from protective to destructive, resulting in increased Tau phosphorylation. This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved α4 are decreased in Opitz syndrome and increased in Alzheimer disease, disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively. These findings indicate that regulated inter-domain cleavage controls the dual functions of α4, and dysregulation of α4 cleavage may contribute to Opitz syndrome and Alzheimer disease.
Highlights
Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs)
This regulatory mechanism appears important in MAP-dependent pathologies as levels of cleaved ␣4 are decreased in Opitz syndrome and increased in Alzheimer disease, disorders characterized by MAP hypophosphorylation and hyperphosphorylation, respectively
MID1 was initially postulated to function as the E3 ubiquitin ligase for PP2A catalytic subunit (PP2Ac) polyubiquitination [1], a recent in vitro study demonstrated that the RING and B-box domains of MID1 possess E3 ligase activity and can monoubiquitinate a 45-amino acid polypeptide derived from the C terminus of ␣4 [12]
Summary
Multiple neurodegenerative disorders are linked to aberrant phosphorylation of microtubule-associated proteins (MAPs). Monoubiquitination of ␣4 promotes calpain-mediated cleavage and switches its activity from protective to destructive toward PP2Ac. Consistent with these results, we observed increased phosphorylation of the microtubule-associated Tau protein in cells overexpressing the N-terminal cleavage product of ␣4 relative to cells overexpressing full-length ␣4.
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