Table 2.

Evidences of proteinopathy for tau vs. MAP2.

Evidence of proteinopathy	Tau	MAP2
Mutation of the encoding gene is associated with disease	Mutations in MAPT gene lead to FTDP-17 as well as other neurodegenerative disorders similar to Pick’s disease, corticobasal degeneration and supranuclear palsy (Strang et al., 2019)	Autism-associated rare 2q34 microdeletions encompass the MAP2 gene (Pescucci et al., 2003); however, mutations selective to MAP2 have not to date been associated with disorder
Modifications of transcript or protein are associated with disease	Tau protein hyperphosphorylation is a hallmark of tauopathy, contributing to its aggregation/formation of NFTs (Noble et al., 2013). Missplicing of Tau pre-mRNA- in some cases associated with MAPT mutation- is also associated with various tauopathies (Park et al., 2016)	Changes in expression, post-translational modification and/or splicing of MAP2 have been described in various disorders (see Table 1)
Experimental manipulation of the protein causes disease-associated pathology	Mutant Tau mouse lines such as rTg4150 can replicate key features of tauopathy including neuron loss and memory impairments (Denk and Wade-Martins, 2009). Phosphomimicry of Tau can lead to learning and memory deficits in Drosophila and mice (Beharry et al., 2013; Di et al., 2016)	MAP2 knockdown can lead to impairments in LTP and dendritic outgrowth, which are implicated in neurodevelopmental and neurodegenerative disorder (Kim et al., 2020). Mimicry of a schizophrenia-associated MAP2 phosphorylation event leads to reduced dendritic arborization and spine density (Grubisha et al., 2021). Other disease-relevant modifications of MAP2, such as altered splicing or cleavage, have not been modeled. Behavioral/cognitive outcomes of mutant MAP2 animals have not yet been reported
Protein dysregulation precedes functional impairments	Tau deposition precedes clinical symptoms of disorder in humans (Jack et al., 2010)	Time course of MAP2 PTMs, splicing alterations, etc remain unknown
Degree of protein dysregulation scales with disease pathology	Burden of tau PET binding correlates with cognitive symptoms and severity of regional atrophy (Cho et al., 2016). Higher NFT burden is also associated with faster cognitive decline (Jefferson-George et al., 2017)	MAP2 phosphopeptide levels correlate with dendritic spine density and socioeconomic status in individuals with schizophrenia (Grubisha et al., 2021). Additionally, MAP2-IR loss statistically mediates dendritic spine loss in primary auditory cortex of subjects with schizophrenia (McKinney et al., 2019). Associations of MAP2 expression/phosphorylation with pathology in other disorders remains uninvestigated

Bold face text highlights current gaps in knowledge regarding MAP2 pathology.