Pumilio1 Haploinsufficiency Leads to SCA1-like Neurodegeneration by Increasing Wild-Type Ataxin1 Levels

Abstract

SUMMARY Spinocerebellar ataxia type 1 (SCA1) is a paradigmatic neurodegenerative proteinopathy, in which a mutant protein (in this case, ATAXIN1) accumulates in neurons and exerts toxicity; in SCA1 this process causes progressive deterioration of motor coordination. Seeking to understand how post-translational modification of ATAXIN1 levels influences disease, we discovered that the RNA-binding protein PUMILIO1 (PUM1) not only directly regulates ATAXIN1 but that it also plays an unexpectedly important role in neuronal function. Loss of Pum1 caused progressive motor dysfunction and SCA1-like neurodegeneration with motor impairment, primarily by increasing Ataxin1 levels. Breeding Pum1+/− mice to SCA1 mice (Atxn1154Q/+) exacerbated disease progression, whereas breeding them to Atxn1+/− mice normalized Ataxin1 levels and largely rescued the Pum1+/− phenotype. Thus, both increased wild-type ATAXIN1 levels and PUM1 haploinsufficiency could contribute to human neurodegeneration. These results demonstrate the importance of studying post-transcriptional regulation of disease-driving proteins to reveal factors underlying neurodegenerative disease.

Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins

“…For example, Pum1 haploinsufficiency results in neurodegeneration in mice due to upregulation of the PUMILIO target Ataxin1 (Gennarino et al, 2015). Our data further document that either increased or decreased PUM1/2 activity results in deleterious consequences.…”

“…Many mammalian PUM targets have been identified using high-throughput approaches (Chen et al, 2012; Galgano et al, 2008; Hafner et al, 2010; Morris et al, 2008), revealing diverse functions for these proteins in germline homeostasis (Chen et al, 2012; Spassov and Jurecic, 2003), cell cycle control (Kedde et al, 2010; Miles et al, 2012) and neuronal activity and function (Driscoll et al, 2013; Vessey et al, 2010). Notably, Pum1 haploinsufficiency in mice has recently been reported to result in neurodegeneration (Gennarino et al, 2015), demonstrating that PUM dosage must be precisely controlled in vivo to avoid significant pathologic consequences. Nevertheless, the mechanisms through which PUM activity is regulated remain unknown.…”

Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration

“…In Alzheimer’s disease, cognition declines with widespread neuronal destruction and in Parkinson’s, Huntington’s, and ataxia movement rapidly deteriorates with the onset of neurodegeneration (Gennarino et al, 2015). However, neurodegeneration may not be a prerequisite for such dysfunction.…”

Molecular functions and biological roles of long non‐coding RNAs in human physiology and disease

“…Remarkably, a new doxycycline inducible transgenic mouse model with enforced PUM2 expression fully recapitulates the aging‐associated phenotypes observed in Norad ‐deficient mice, demonstrating that the downstream effects of Norad loss‐of‐function are mediated by hyperactivity of PUMILIO proteins. These findings, together with recent reports showing that even slightly reduced PUM1 protein levels lead to neurodegenerative phenotypes in humans and mice, demonstrate that PUMILIO activity and levels must be kept within a narrow range to avoid deleterious effects on mammalian physiology. NORAD has likely evolved in the mammalian lineage to provide an efficient mechanism to precisely titrate the pool of free PUMILIO proteins upon varying cellular demands.…”