Vignesh Subramanian ’24

Huntington’s disease (HD) is an inherited neurodegenerative disease that causes the progressive breakdown of neurons over time, resulting in the development of involuntary movements (chorea), psychiatric disorders, and cognitive decline. HD is caused by the dominant mutation of the HTT gene encoding huntingtin, a protein whose normal function is unknown but is linked to projection neuron death in the striatum of the brain, a key node of motor control, reward learning, and repetitive behaviors. The most abundant type of striatal neuron is known as medium-sized spiny neurons (MSNs), which die first and predominantly in HD. Ordinarily, a natural degradation process known as autophagy would recycle these dysfunctional cells before they uncontrollably degenerate and accumulate; it remains unknown whether the failure of this process to occur is coincidental or causative of MSNs’ extreme vulnerability. Researchers led by Dr. Young Oh thus worked to characterize the influence of autophagy impairment on MSNs’ predisposition to pathological degeneration. 

The researchers used direct neuronal reprogramming, a novel method of converting somatic cells to induced neurons without passing through a pluripotent state, to model the pathway of preferential MSN degeneration. Dermal fibroblast cells were converted to MSN lineages using select microRNAs, transferring the ‘age information’ of the initial somatic cells (such as the epigenetic clock and age-associated transcriptome changes) to the induced neurons and making modeling of age-related HD progression in patients of different age ranges and disease stages possible. Finally, researchers developed a new analog of a drug known to enhance autophagy mechanisms– referenced as G2-115– to determine whether its application could reverse MSN degeneration.

The researchers found that HD-MSNs demonstrated reduced chromatin accessibility at several autophagy genes as compared to pre-symptomatic HD-MSNs, suggesting that regulatory elements, which rely on chromatin accessibility to control gene transcription, were less capable of initiating autophagy and senescence of degenerating MSNs. Conversely, HD-MSNs demonstrated increased chromatin accessibility at the host gene of a mature microRNA that was expressed at significant levels in older, symptomatic HD patients. The microRNA was also implicated by assay analysis and knockdown experiments in the direct suppression of natural autophagy by targeting regulatory gene STAT3. Subsequent G2-115 treatment of the affected reprogrammed neurons protected them from death, with higher doses having stronger effects. 

This study thus conclusively identified an age- and autophagy impairment-correlated pathway responsible for the onset of striatal neuron degeneration in HD, while highlighting a potential therapeutic means of counteracting its progression. 

Works Cited:

[1] Y. Oh, et al., Age-related Huntington’s disease progression modeled in directly reprogrammed patient-derived striatal neurons highlights impaired autophagy. Nature Neuroscience 25, 1-29 (2022). doi: 10.1038/s41593-022-01185-4

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:Z_MaxProjection_of_MediumSpinyNeurons_Gpr101Cre_dtTomato.jpg