Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is caused by polyalanine expansion in nuclear protein PABPN1 [poly(A) binding protein nuclear 1] and characterized by muscle degeneration. Druggable modifiers of proteotoxicity in degenerative diseases, notably the longevity modulators sirtuins, may constitute useful therapeutic targets. However, the modifiers of mutant PABPN1 are unknown. Here, we report that longevity and cell metabolism modifiers modulate mutant PABPN1 toxicity in the muscle cell. Using PABPN1 nematodes that show muscle cell degeneration and abnormal motility, we found that increased dosage of the sirtuin and deacetylase sir-2.1/SIRT1 exacerbated muscle pathology, an effect dependent on the transcription factor daf-16/FoxO and fuel sensor aak-2/AMPK (AMP-activated protein kinase), while null mutants of sir-2.1, daf-16 and aak-2 were protective. Consistently, the Sir2 inhibitor sirtinol was protective, whereas the Sir2 and AMPK activator resveratrol was detrimental. Furthermore, rescue by sirtinol was dependent on daf-16 and not aak-2, whereas aggravation by resveratrol was dependent on aak-2 and not daf-16. Finally, the survival of mammalian cells expressing mutant PABPN1 was promoted by sirtinol and decreased by resveratrol. Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases.

Neuron Dysfunction Is Induced by Prion Protein with an Insertional Mutation via a Fyn Kinase and Reversed by Sirtuin Activation inCaenorhabditis elegans

“…Sirtuins are key longevity/cell survival modulators, and their manipulation is neuroprotective in several models of degenerative disease pathogenesis including Wallerian degeneration (Araki et al, 2004), HD (Parker et al, 2005), microglia-mediated amyloid-␤ toxicity (Chen et al, 2005), Alzheimer's disease/ tauopathies and amyotrophic lateral sclerosis (Kim et al, 2007), ␣-synuclein toxicity (Outeiro et al, 2007), and OPMD (Catoire et al, 2008). It is intriguing that in models of expanded polyglutamine toxicity (HD), increased sir-2.1/SIRT1 dosage protects diseased cells (Parker et al, 2005), whereas in models of expanded polyalanine toxicity (OPMD), it is detrimental to cell survival, with sir-2.1/SIRT1 inhibition being beneficial (Catoire et al, 2008).…”

“…It is intriguing that in models of expanded polyglutamine toxicity (HD), increased sir-2.1/SIRT1 dosage protects diseased cells (Parker et al, 2005), whereas in models of expanded polyalanine toxicity (OPMD), it is detrimental to cell survival, with sir-2.1/SIRT1 inhibition being beneficial (Catoire et al, 2008). It is also intriguing that both SIRT1 activation (Chen et al, 2005;Parker et al, 2005) and SIRT2 inhibition (Outeiro et al, 2007) may be neuroprotective.…”

“…Whether sirtuins may be activated or inhibited to achieve neuroprotection is still debated (Dillin and Kelly, 2007). Since sirtuins belong to a network of genes that is finely tuned in response to stress (Brunet et al, 2004), the net outcome of manipulating sirtuins in diseased cell protection may be greatly influenced by (1) the sirtuin being manipulated (SIRT1, SIRT2, and SIRT3 have different subcellular localizations and activities), (2) the level of acetylation of the sirtuin targets that are affected by the pathology (Catoire et al, 2008), and (3) the strength of cellular stress (cell death vs cell dysfunction) induced in the model system (Parker et al, 2005;Pallos et al, 2008). Regarding sirtuins and prions, it was recently reported by Chen et al (2008) that the onset of disease induced by infection of mice with the RML prion strain is delayed in SIRT1 KO mice.…”

“…including Huntington's disease (Parker et al, 2005), microgliadependent amyloid ␤ toxicity (Chen et al, 2005), inherited Parkinson's disease (Outeiro et al, 2007), and oculopharyngeal muscular dystrophy (OPMD) (Catoire et al, 2008). The LOF mutant sir-2.1(ok434 ) enhanced neuronal dysfunction induced by PG13-PrP expression with no effect detected in animals expressing Wt-PrP (Fig.…”

Modeling Oculopharyngeal Muscular Dystrophy in Myotube Cultures Reveals Reduced Accumulation of Soluble Mutant PABPN1 Protein

“…[17][18][19][20] In these animal model systems, anti-aggregation treatments reduced muscle symptoms and INI formation 19,21,22 ; how-ever, the molecular mechanisms by which expPABPN1 is toxic to cells have not been fully elucidated. Increased frequency of cell death is found in animal and cellular models with expPABPN1 overexpression, 9 but cell death and overexpression of expPABPN1 have not been reported in heterozygous patients with OPMD.…”