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The genetic basis of neurodegenerative disease discovered


A new study by researchers at the University of California at Irvine has confirmed a link between impaired DNA repair and increased DNA damage associated with spinocerebellar ataxia type 7 (SCA7), a debilitating, sometimes fatal, neurodegenerative disease causing movement disorders. Their work also revealed a potential therapeutic target for the currently incurable and difficult to treat disease.

Entitled, “Altered H3 histone acetylation alters high fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7”, The study was published today in Cell reports.

“Our research explores the mechanistic basis for the degeneration and death of cerebellar neurons in SCA7, a specific ACS that causes impaired coordination, such as difficulty walking, speaking and moving the eyes,” said the corresponding author Albert La Spada, professor emeritus of pathology, neurology and biological chemistry at the UCI Faculty of Medicine. “Through our efforts, we have confirmed the link between impaired DNA repair and DNA damage, as well as the importance of the activation of PARP1 enzymes that results.”

Previous research has shown that increased DNA damage can lead to the activation of PARP1 enzymes. These enzymes serve to recruit the DNA repair machinery, but can also promote the dysfunction and death of cerebellar neurons. Fortunately, PARP inhibitors already exist and could prove to be a promising potential new treatment.

“What is perhaps more exciting is that the DNA damage and altered DNA repair found in SCA7 is also found in other ACS. This could mean that new therapies to treat the devastating effects of many forms of spinocerebellar ataxia could be possible, ”said LaSpada. “Our next steps will be to test candidate PARP inhibitor drugs in mouse models of SCA7 as well as in neurons derived from pluripotent stem cells generated from human SCA7 patients. “

SCA7, belongs to a category of disease that includes spinobulbar muscular atrophy (SBMA), Huntington’s disease (HD), dentatorubral-pallidoluyseal atrophy (DRPLA) and five other forms of spinocerebellar ataxia (SCA1, 2, 3 , 6 and 17).

Each year, 15,000 to 20,000 Americans suffer from spinocerebellar ataxia (SCA), a genetic inherited neurodegenerative disease, which frequently results in atrophy of the cerebellum and loss of fine coordination of muscle movements resulting in unstable and awkward movements, and d ‘other symptoms. ACS can affect anyone of any age. Currently, there is no known effective treatment or cure.

Reference: Switonski PM, Delaney JR, Bartelt LC, et al. Altered H3 histone acetylation alters high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7. Cell representative. 2021; 37 (9). do I: 10.1016 / j.celrep.2021.110062

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