MAP2, short for Microtubule-associated protein 2, is a crucial cytoskeletal regulator within neuronal dendrites [2,3,4,6]. It is involved in influencing microtubule dynamics and microtubule/actin interactions, which are essential for neurite outgrowth and synaptic functions [6]. MAP2 is also rich in PEST sequences, making it susceptible to protease attack, and its phosphorylation can change its structure and function [3].

In Alzheimer's disease-related research, MAP2 monomers can bind to the end of tau fibrils, blocking the spontaneous and seeded aggregation of 4R tau in vitro, in HEK293 cells, and in AD brain extracts, suggesting it may modulate tau propagation [1]. In schizophrenia studies, MAP2 is differentially phosphorylated. For example, phosphorylation at serine 1782 reduces its binding to microtubules. A transgenic mouse with a phosphomimetic mutation at S1782 (S1782E) shows reduced basilar dendritic length, complexity, and spine density. Also, the MAP2 interactome is disrupted in S1782E mice, with reduced interactions with certain proteins potentially linked to schizophrenia pathogenesis [2,7]. In Huntington's disease, there is a splicing alteration of MAP2, leading to a disbalance in its mRNA isoforms and a decrease in total MAP2 protein, which may contribute to dendritic atrophy [5].

In conclusion, MAP2 is essential for neuronal structure and function. Studies using transgenic mouse models (such as the S1782E mouse model in schizophrenia research) have revealed its role in diseases like Alzheimer's, schizophrenia, and Huntington's disease. These models help us understand how MAP2 dysregulation can lead to impairments in neuronal structure, synaptic function, and contribute to disease pathogenesis.

References:

1. Holden, Michael R, Krzesinski, Brad J, Weismiller, Hilary A, Shady, Justin R, Margittai, Martin. 2023. MAP2 caps tau fibrils and inhibits aggregation. In The Journal of biological chemistry, 299, 104891. doi:10.1016/j.jbc.2023.104891. https://pubmed.ncbi.nlm.nih.gov/37286038/

2. Grubisha, M J, Sun, X, MacDonald, M L, Ding, Y, Sweet, R A. 2021. MAP2 is differentially phosphorylated in schizophrenia, altering its function. In Molecular psychiatry, 26, 5371-5388. doi:10.1038/s41380-021-01034-z. https://pubmed.ncbi.nlm.nih.gov/33526823/

3. Friedrich, P, Aszódi, A. . MAP2: a sensitive cross-linker and adjustable spacer in dendritic architecture. In FEBS letters, 295, 5-9. doi:. https://pubmed.ncbi.nlm.nih.gov/1765166/

4. DeGiosio, R A, Needham, P G, Andrews, O A, Camacho, C, Sweet, R A. . Differential regulation of MAP2 by phosphorylation events in proline-rich versus C-terminal domains. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 37, e23194. doi:10.1096/fj.202300486R. https://pubmed.ncbi.nlm.nih.gov/37702880/

5. Cabrera, Jorge Rubén, Lucas, José J. 2016. MAP2 Splicing is Altered in Huntington's Disease. In Brain pathology (Zurich, Switzerland), 27, 181-189. doi:10.1111/bpa.12387. https://pubmed.ncbi.nlm.nih.gov/27098187/

6. DeGiosio, Rebecca A, Grubisha, Melanie J, MacDonald, Matthew L, Camacho, Carlos J, Sweet, Robert A. 2022. More than a marker: potential pathogenic functions of MAP2. In Frontiers in molecular neuroscience, 15, 974890. doi:10.3389/fnmol.2022.974890. https://pubmed.ncbi.nlm.nih.gov/36187353/

7. Lyu, Jiali, MacDonald, Matthew L, Ruiz, Shelby, Grubisha, Melanie J, Sweet, Robert A. 2024. Deciphering the alteration of MAP2 interactome caused by a schizophrenia-associated phosphorylation. In Neurobiology of disease, 203, 106731. doi:10.1016/j.nbd.2024.106731. https://pubmed.ncbi.nlm.nih.gov/39532265/