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Autophagy May Be the Key to Finding Treatments for Early Huntington’s Disease

Autophagy disruption may be at the root of early cognitive changes in Huntington’s disease and is a potential target for disease-modifying therapies, report scientists in JHD

July 15, 2021
Amsterdam, NL – Huntington’s Disease (HD) is a progressive neurodegenerative condition characterized by motor, cognitive, and psychiatric symptoms, and motor symptoms are often preceded by cognitive changes. Recent evidence indicates that autophagy plays a central role in synaptic maintenance, and the disruption in autophagy may be at the root of these early cognitive changes. Understanding this mechanism better may help researchers develop treatments for patients with HD early in their disease progression, report scientists in a review article published in the Journal of Huntington’s Disease.

In this review, experts describe how autophagy, the cellular process responsible for clearing old or damaged parts of the cell, plays a critical role supporting synaptic maintenance in the healthy brain, and how autophagy dysfunction in HD may thereby lead to impaired synaptic maintenance and thus early manifestations of disease. The line of research discussed in this review represents a previously unexplored avenue for identifying potential disease-modifying therapies for HD.

“Like many neurodegenerative conditions affecting primarily cognition, such as Alzheimer’s disease, preclinical and clinical data indicate that synapses, the part of brain cells responsible for communication between cells, are affected early in HD,” explained Hilary Grosso Jasutkar, MD, PhD, Department of Neurology, Columbia University, and Ai Yamamoto, PhD, Departments of Neurology and Pathology and Cell Biology, Columbia University, New York, NY, USA. “We have long thought that autophagy played a role in the pathophysiology of HD, but what this role is has been unclear until recently. Recent evidence indicates that autophagy may be important in maintaining the synapse. This line of research has the potential to lead to identification of a drug target to treat HD early in the disease process.”

The authors first explore how cognitive dysfunction is an early manifestation of HD, and that similarly to other neurodegenerative diseases that primarily affect cognition, such as Alzheimer’s disease, dementia with Lewy bodies, and frontotemporal dementia, early deficits in synaptic function may underlie these cognitive symptoms. Next, they review the growing evidence that the lysosome-mediated degradation pathway autophagy plays a central role in synaptic maintenance, and how the disruption in autophagy may contribute to early cognitive changes in HD.

Caption: Proposed pathway of mutant huntingtin (mHtt) contribution to cognitive dysfunction and cell death through impairments in synaptic autophagy: the Huntingtin protein (mHtt) interferes with autophagic efficiency, leading to a decline in synaptic autophagy. This may in turn interfere with synaptic plasticity, causing both cognitive dysfunction and loss of normal synaptic input to post-synaptic cells and feedback to presynaptic cells. Loss of normal synaptic feedback and input may then contribute to cell death (credit: H. Grosso Jasutkar and A. Yamamoto).

The authors conclude that there are pathologic and imaging data in individuals with mutations in the Huntingtin protein (mHtt), as well as evidence from animal models with HD, that suggest that synapse dysfunction may occur early in HD, prior to cell death.

“Autophagy plays a specialized role in the maintenance and function of the synapse, and mHtt may disrupt this function, leading to the early synaptic changes seen in HD patients and model systems,” explained Dr. Grosso Jasutkar. “These synaptic changes may then manifest as impairments in synaptic plasticity and thus cognitive changes early in the disease course. Given that neurons rely on synaptic input and feedback for cell health, it is possible that this disruption in synaptic signaling in and of itself contributes to cell death in HD.”

“There is much work yet to be done in this field,” added Dr. Yamamoto. “Although various groups have demonstrated individual components of this pathway, a direct causal relationship of mutant Htt leading to synaptic dysfunction and, in turn, cognitive impairments, has yet to be demonstrated.”

“If the model described here is borne out, therapeutics aimed at enhancing the efficiency of synaptic autophagy early in the course of HD could be protective against early cognitive changes and potentially degeneration itself,” concluded the authors.

HD is a fatal genetic neurodegenerative disease that causes the progressive breakdown of nerve cells in the brain. An estimated 250,000 people in the United States are either diagnosed with, or at risk for, the disease. Symptoms include personality changes, mood swings and depression, forgetfulness and impaired judgment, unsteady gait, and involuntary movements (chorea). Every child of an HD parent has a 50% chance of inheriting the gene. Patients typically survive 10–20 years after diagnosis.

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NOTES FOR EDITORS
Full open access study: “Do Changes in Synaptic Autophagy Underlie the Cognitive Impairments in Huntington’s Disease?” by Hilary Grosso Jasutkar and Ai Yamamoto (DOI: 10.3233/JHD-200466) in the Journal of Huntington’s Disease, Volume 10, Issue 2 published by IOS Press. View the open access article at: content.iospress.com/articles/journal-of-huntingtons-disease/jhd200466.

Hilary Grosso Jasutkar is an appointee on the Research Training in Late-Life NeuroPsychiatric Disorders T32 grant held by Columbia University Department of Psychiatry, through NIMH, PI Dr. Steven Roose, grant #5T32MH020004-2. Ai Yamamoto is supported by the Hereditary Disease Foundation, Thompson Family Foundation, and NINDS (R01 NS077111, NS063973).

Contact
Contact Diana Murray, IOS Press (+1 718-640-5678 or d.murray@iospress.com) for additional information. Journalists who wish to interview the authors should contact Ai Yamamoto (ay46@cumc.columbia.edu).

About the Journal of Huntington’s Disease
The Journal of Huntington’s Disease (JHD) is an international multidisciplinary journal to facilitate progress in understanding the genetics, molecular correlates, pathogenesis, pharmacology, diagnosis and treatment of Huntington’s disease and related disorders. The journal publishes research reports, reviews, short communications, letters-to-the-editor, and will consider research that has negative findings. JHD is dedicated to providing an open forum for original research in basic science, translational research, and clinical medicine that will expedite our fundamental understanding and improve treatment of Huntington’s disease and related disorders. iospress.com/journal-of-huntingtons-disease

About IOS Press
IOS Press is headquartered in Amsterdam with satellite offices in the USA, Germany, India and China and serves the information needs of scientific and medical communities worldwide. IOS Press now publishes more than 90 international peer-reviewed journals and about 65 book titles each year on subjects ranging from computer science, artificial intelligence, and engineering to medicine, neuroscience, and cancer research. iospress.com