Mitochondrial Therapy: New Hope in Treating Huntington's Disease
What is Huntington’s Disease?
Huntington’s Disease (HD) is a neurodegenerative disorder that is passed down in families and is caused by a dominant mutation in the HTT gene on chromosome 4.1 HD affects approximately 1 in 7000 Canadians, and there is no known cure.2 While the function of the protein responsible for HD has not been elucidated, its dysfunction results in very severe neurological damage initially manifesting itself as a loss of voluntary motor skills, which is then followed by rapid cognitive decline and mental instability that eventually leads to death when the autonomic nervous system responsible for controlling breathing and heartbeat shut down.1 Symptoms generally begin appearing between the ages 30-50, and include involuntary movement (chorea), cognitive and behavioural decline (dementia), mood changes, and obsessive compulsive disorder (OCD).3 Prognosis is very poor as there is no treatment, which leads to death within 10 to 30 years, although quality of life deteriorates relatively quickly after symptom onset.
Current treatment methods
As there is no cure, treatment methods are geared towards managing the aforementioned symptoms. Chorea is treated with atypical antipsychotic medications, such as olanzapine, or with tetrabenazine, an HD-specific drug.3 For less severe mood changes and OCD, antidepressants known as selective serotonin reuptake inhibitors are recommended. However, for more severe mood changes that elicit threatening behavior, atypical antipsychotics are again recommended.3 Cognitive and behavioral decline may be slowed through exercise, social activity, a healthy diet, and intellectual stimulation; however, the neurodegeneration caused by HD is irreversible.4
Mitochondrial function in HD neurons
Pathological neurodegeneration in HD is hypothesized to be worsened by mitochondrial dysfunction.5 Mitochondria are cell components essential for converting glucose to ATP, an energy molecule used by neurons (brain cells), which also plays a role in fat metabolism and reactions involving oxygen.5 The ATP generated by the mitochondria are required by neurons to survive and send signals to keep the body functioning. Therefore, mitochondrial dysfunction is thought to promote neurodegeneration, which is the progressive loss of organ function due to neuronal death. Evidence supports that it is an early indicator of neurons that may be susceptible to HD.5
Mitochondrial therapy
No therapies exist that prevent disease progression, but recent studies from Case Western Reserve University School of Medicine show that mitochondria-targeting therapy may be beneficial in reducing HD-related neuropathology. In an animal study published in 2021, the HTT gene from humans was transferred into the mice, and CHIR99021 and calpastatin (CAST) were identified as molecules relevant in the pathology of HD.5 Identifying these cell signaling molecules associated with HD is especially important as they represent the best, most effective targets for possible treatments. CHIR99021 was found to enhance mitochondrial function and improve the survival of neurons when administered to the mice which had HD.5 After 3 months of CHIR99021 administration, these mice exhibited improved motor control, and long-term administration reduced neuropathology and motor control deficit progression.5 CHIR99021 restored mitochondrial function by stabilizing CAST.5 CAST is an inhibitor of calpain, a molecule that exacerbates neuron death, and it is also a regulator of Drp1, a molecule that causes mitochondrial dysfunction.5 CAST stabilization by CHIR99021 was found to prevent CAST degradation, and subsequently, Drp1 action.5 The study showed that CHIR99021 treatment restored CAST in HD mice to healthy levels, showing promise for the CAST-Drp1 pathway being a new target in HD treatment.5
Future development
Mitochondrial damage is an understudied aspect of HD pathogenesis, so the recent findings on CHIR99021 administration incited new hope for slowing the progression of HD. Further research on calpastatin stabilizing CHIR99021-like molecules, as well as testing on human subjects, could accelerate treatment research and eventually lead to a potential therapy for HD neurodegeneration.
Esther ChangReferences:
1. Paulsen JS. Cognitive impairment in Huntington's disease: diagnosis and treatment. Curr Neurol Neurosci Rep. 2011; 11(5): 474-483. doi: 10.1007/s11910-011-0215-x
2. Advancing towards treatment for Huntington's disease. Brain Canada. https://braincanada.ca/research-stories/advancing-towards-treatment-for-huntingtons- disease/. Published October 11, 2017. Accessed November 15, 2021.
3. Huntington's disease. Alzheimer's Disease and Dementia. https://www.alzheimers.org.uk/about-dementia/types-dementia/huntingtons-disease. Accessed November 15, 2021.
4. Managing older patients with cognitive impairment. National Institute on Aging. https://www.nia.nih.gov/health/managing-older-patients-cognitive-impairment. Accessed November 15, 2021.
5. Hu D, Sun X, Magpusao A, et al. Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease. Nat Commun. 2021; 12(1): 5305. doi: 10.1038/s41467-021-25651-y
Cite This Article:
Chang E., Suthakaran A., Kozak A., Charron B., Merchant A., Chharawala V., Dmitriev A., Lombo L. Mitochondrial therapy: new hope in treating Huntington’s disease. Illustrated by Jung E. Rare Disease Review. August 2024. DOI: 10.13140/RG.2.2.20313.43361
