Studies in both mice models and Drosophila models have shown that heat shock proteins 40 and 70 may reduce toxicity of expanded ataxin 1 proteins and slow progression of SCA1.While there is currently no known method for exclusively promoting polyglutamine contractions in vivo, techniques using programmable nucleases have shown some promise in causing these changes in vitro. Programmable nucleases are proteins that can break DNA strands near sequences that can be specified by scientists before use. This includes CRISPR/Cas9, which uses a protein found in bacteria and guide strand of RNA, and zinc finger nucleases, which use engineered proteins with special recurring DNA binding domains to guide an attached nuclease. A study reports that both CRISPR and Zinc fingers nucleases that rely on double strand breaks trigger contractions and expansions with nearly equal frequency, while CRISPR using a mutant variation of Cas9, Cas9 D10A or Cas9 nickase, which causes only single strand breaks, produced mainly contractions.In mice, mitochondrial impairments contribute to SCA1 progression. Prominent alterations in Purkinje cell mitochondrial proteins coincide with the symptomatic phase of the disease. Purkinje cells in SCA1 mice also undergo age-dependent alterations in mitochondrial morphology. In addition, Purkinje cells of SCA1 mice have impaired electron transport complexes and decreased ATPase activity. The SCA1 mice experience increased oxidative stress and increased oxidative DNA damage. The mitochondrial targeted antioxidant MitoQ was found to slow down the appearance of SCA1-linked neuropathologies such as lack of motor coordination. MitoQ also prevented oxidative stress induced DNA damage and Purkinje cell loss.
Erythropoietic protoporphyria (EPP) has similar symptoms as X-linked dominant erythropoietic protoporphyria but the mutation occurs as a loss-of-function in the FECH (ferrochelatase) enzyme; the very last enzyme in the pathway. All individuals studied presented symptoms without mutations in the FECH enzyme. The patterns of inheritance led the researchers to conclude the mutation must come from an enzyme on the X-chromosome with ALAS2 being the most likely candidate. X-linked dominant erythropoietic protoporphyria is distinct from EPP in that there is no overload of Fe2+ ions. Additionally, unlike the other condition the arises out of a mutation of the ALAS2 gene, there is no anaemia. XDEPP is characterized by a buildup of protoporphyrin IX caused by in increased level of function in the ALAS2 enzyme. Because there is a buildup of protoporphyrin IX with no malfunction of the FECH enzyme, all the available Fe2+ is used in the production of heme, causing the FECH enzyme to use Zn2+ in its place,  causing a buildup of zinc-protoporphyrin IX. Diagnosis
See also
Hepatic porphyria

References


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