More than a marker: potential pathogenic functions of MAP2

Abstract

Microtubule-associated protein 2 (MAP2) is the predominant cytoskeletal regulator within neuronal dendrites, abundant and specific enough to serve as a robust somatodendritic marker. It influences microtubule dynamics and microtubule/actin interactions to control neurite outgrowth and synaptic functions, similarly to the closely related MAP Tau. Though pathology of Tau has been well appreciated in the context of neurodegenerative disorders, the consequences of pathologically dysregulated MAP2 have been little explored, despite alterations in its immunoreactivity, expression, splicing and/or stability being observed in a variety of neurodegenerative and neuropsychiatric disorders including Huntington's disease, prion disease, schizophrenia, autism, major depression and bipolar disorder. Here we review the understood structure and functions of MAP2, including in neurite outgrowth, synaptic plasticity, and regulation of protein folding/transport. We also describe known and potential mechanisms by which MAP2 can be regulated via post-translational modification. Then, we assess existing evidence of its dysregulation in various brain disorders, including from immunohistochemical and (phospho) proteomic data. We propose pathways by which MAP2 pathology could contribute to endophenotypes which characterize these disorders, giving rise to the concept of a "MAP2opathy"-a series of disorders characterized by alterations in MAP2 function.

Keywords: MAP2; cytoskeleton; neurodegeneration; neurodevelopment; psychiatric disorder.

Figure 1

Domains of MAP2 and homology to MAP Tau. (A) Diagram depicting the domains of the four major isoforms of MAP2. Microtubule (MT)-binding repeats are denoted by black rectangles. Note that an additional MT binding repeat (MBR; gray box) is present in the low molecular weight (LMW) isoform MAP2D. Tau is also shown for size comparison. (B) Protein BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi) alignment of the C-terminus (highlighted region of MAP2B in A) from MAP2B (Uniprot P11137-1; top) and 2N4R Tau (P10636-8; bottom). The MT-binding repeat sequences for each protein are indicated with solid boxes. The middle row indicates homologous or similar (+) residues. MAP2B S1782 (mentioned in the text) is highlighted in red. Figure generated in Microsoft Powerpoint.

Figure 2

Hypothesized model of “MAP2opathy”. Genetically- or environmentally-precipitated upstream risk factors are expected to affect MAP2 in a variety of ways, leading to diverse, overlapping cellular consequences. Thick arrows indicate causal relationships established in in vivo models (Harada et al., ; Kim et al., ; Grubisha et al., 2021). Thin arrows indicate noted correlational relationships (Pettigrew et al., ; Guo et al., ; Cabrera and Lucas, 2017). Figure generated in Microsoft Powerpoint.