Mutations in the Microtubule-Associated Protein 1A (Map1a) Gene Cause Purkinje Cell Degeneration

Abstract

The structural microtubule-associated proteins (MAPs) are critical for the organization of neuronal microtubules (MTs). Microtubuleassociated protein 1A (MAP1A) is one of the most abundantly expressed MAPs in the mammalian brain. However, its in vivo function remains largely unknown. Here we describe a spontaneous mouse mutation, nm2719, which causes tremors, ataxia, and loss of cerebellar Purkinje neurons in aged homozygous mice. The nm2719 mutation disrupts the Map1a gene. We show that targeted deletion of mouse Map1a gene leads to similar neurodegenerative defects. Before neuron death, Map1a mutant Purkinje cells exhibited abnormal focal swellings of dendritic shafts and disruptions in axon initial segment (AIS) morphology. Furthermore, the MT network was reduced in the somatodendritic and AIS compartments, and both the heavy and light chains of MAP1B, another brain-enriched MAP, was aberrantly distributed in the soma and dendrites of mutant Purkinje cells. MAP1A has been reported to bind to the membrane-associated guanylate kinase (MAGUK) scaffolding proteins, as well as to MTs. Indeed, PSD-93, the MAGUK specifically enriched in Purkinje cells, was reduced in Map1a Ϫ/ Ϫ Purkinje cells. These results demonstrate that MAP1A functions to maintain both the neuronal MT network and the level of PSD-93 in neurons of the mammalian brain.

Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice

“…PC hypertrophy was also observed in mice lacking TSC1 or TSC2 in PCs (Tsai et al, 2012;Reith et al, 2011), which are downstream targets of the PTEN/PI3K pathway. Intriguingly, in our model PTEN appears to have a critical role in modulating the organization/distribution of microtubule networks in the PC dendritic compartment, which are pivotal for normal dendritic morphology, intracellular transport and neuronal survival (Liu et al, 2015).…”

“…Abnormal focal swellings of dendritic shafts (accompanied by abnormally high levels of the microtubule-associate protein MAP1B and tubulins), axonal torpedoes and neuronal degeneration have been observed in PCs of mutant mice lacking MAP1A (Liu et al, 2015). The presence of similar dendritic and axonal features in PTEN mutant PCs prompted us to investigate the organization of cytoskeletal components, such as microtubules and neurofilaments.…”

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals

“…18 Though typically examined in a neurological context, MAP1A is involved in microtubule assembly, a process important in blood cell development and function. 68 Our observed association of MAP1A and its expression in platelets and RBCs suggests that the known role of MAP1A in developmental and cytoskeletal processes in neural tissues may extend to blood cells (Table S22). How these shared genetic factors specifically influence the development, maintenance, or clearance of multiple blood cell types remains to be determined.…”

“…Loos, 13 Albert Vernon Smith, 59,60 Tamara B. Harris, 61 Lenore J. Launer, 61 Vilmundur Gudnason, 59,60 Digna R. Velez Edwards, 62 Eric S. Torstenson, 19 Yongmei Liu, 63 Russell P. Tracy, 64 Jerome I. Rotter, 65,66 Stephen S. Rich, 22 Heather M. Highland, 67,68 Eric Boerwinkle, 18,69 Jin Li, 70 Ethan Lange, 21,71 James G. Wilson, 72 Evelin Mihailov, 73 Reedik Mägi, 73 Joel Hirschhorn, 7,74 Andres Metspalu, 73 Tõnu Esko, 7,73 Caterina Vacchi-Suzzi, 75 Mike A. Nalls, 76 Alan B. Zonderman, 12 Michele K. Evans, 12 Gunnar Engström, 77,78 Marju Orho-Melander, 77 We thank all participants and study coordinating centers. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the NIH, or the U.S. Department of Health and Human Services.…”

Increase in α-tubulin modifications in the neuronal processes of hippocampal neurons in both kainic acid-induced epileptic seizure and Alzheimer’s disease

“…In the soma and the main shaft of Purkinje neurons, glutamylated tubulin detected by GT335 is likely to be mostly tyrosinated or detyrosinated forms. Indeed, both glutamylated tubulin and tyrosinated tubulin have been strongly detected in soma and the main shaft of Purkinje neurons40. In contrast, parallel fibres and climbing fibres have some populations of Δ2-tubulin that seem to undergo glutamylation with glutamate chains of optimal length for DTE41.…”