Our novel findings on poly(Q) diseases and Insulin Signalling
The term “neurodegenerative disorders” refers to a large group of diseases which are caused by the deterioration of the neurons of the human brain. Most of these disorders encompass a progressive loss of the structure and function of neuronal cells and often, neuronal demise. [Poly(Q)] disorders such as Huntington’s disease, Spinocerebellar ataxia(s) (SCAs), Spinal and Bulbar Muscular Atrophy (SBMA) etc. represents a subgroup of such shattering neurodegenerative illnesses which manifest owing to a “trinucleotide repeat expansion” in the coding DNA sequence of the affected gene (such as ‘huntingtin’ gene in case of Huntington’s disease). The term “expansion” refers to the increased number of trinucleotide repeats (such as increased number of CAG repeats in DNA sequence of patient’s huntingtin gene, compared to the normal individual) in the mutated gene as compared to its normal counterpart. Interestingly, when the number of such triplet repeats in affected individual extends beyond a critical threshold (generally over 40 repeats), it overrides all genomic safeguards and leads to toxicity due to abnormal folding of the encoded protein. In over 50% of the trinucleotide repeat disorders known till date, the expansion is found to be of the CAG trinucleotide that would code for the amino acid glutamine (denoted by the letter “Q”) when present in the coding region of the affected gene, and therefore, these group of disorders are referred to as polyglutamine or poly(Q) disorders.
Pathogenesis of poly(Q) disorders initiates from abnormal folding of the mutant protein (i.e. mutant Huntingtin protein in case of Huntington’s disease), which form small aggregates in the brain neuronal cells and progressively sequester other important proteins those are essential for normal cellular function and survival, and while doing so, the aggregates grow in size. Such toxic protein aggregated are known as Inclusion Bodies (IBs). Occurrence of inclusion bodies in the neuronal cells is considered as pathological hallmark of all poly(Q) disorders. Due to sequestration of important proteins in these neurotoxic inclusion bodies, the transcription machinery (RNA coding capacity of a cell) of the neuronal cells collapse, and subsequently causes neuronal cell death or brain degeneration.
Our comprehensive investigations revealed that insulin signalling pathway, which is a critical controller of cellular metabolism and energy homeostasis is severely compromised in Huntington’s disease or poly(Q) disease condition. Following a comprehensive genetic screening and by enhancing the level of insulin signalling by upregulating the insulin receptor in the disease affected neuronal cells, we found for the first time that enhanced/improved insulin signalling in the brain neuronal cells can dominantly restrict the pathogenesis of poly(Q) diseases such as Huntington’s and other diseases as mentioned above.
While unrevealing the operative molecular mechanism, we noted that enhanced level of insulin signalling pathway in poly(Q) disease background resulted significant reduction in the cellular level of neurotoxic protein aggregates or inclusion bodies, and a remarkable decrease in the neuronal cell death was also evident. Therefore, it appears that increased insulin signalling in the disease condition inhibits formation of protein aggregates in the neuronal cells, and while doing so, it restricts the disease pathogenesis and neurodegeneration.
Our in-depth investigations to reveal the mechanistic details further suggests that enhanced level of insulin signalling in poly(Q) disease background restores the cellular transcription machinery in the neuronal cells, which was otherwise collapsed due to diseased condition. The insulin signalling mediated restoration of cellular transcription machinery is largely achieved by enriching the cellular pool of several important proteins (such as transcription factors) which are essential for cellular functioning and survival. As noted earlier, these critical proteins are otherwise get sequestered in the inclusion bodies and not available for cellular functioning in the disease condition. We found that the improved cellular pool of such important proteins due to enhanced level of insulin signalling restores back the cellular metabolism and energy homeostasis. It appears that enhanced level of insulin signalling rejuvenates the neuronal cells which are otherwise stressed during disease condition. In view of above, our findings strongly suggests that anti-diabetic drugs could be efficiently utilized to restrict the pathogenesis of poly(Q) disorders, such as Huntington’s disease, Spinocerebellar ataxia(s) (SCAs), Spinal and Bulbar Muscular Atrophy (SBMA) etc.
Taken together, we report for the first time that modulation of insulin signalling pathway can be exploited as a novel approach to treat the human neurodegenerative disorders. Therefore, our findings could be immensely useful for novel drug development and therapeutic intervention against devastating human brain illnesses.
Raj K, Sarkar S. (2018) Tissue-Specific Upregulation of Drosophila Insulin Receptor (InR) Mitigates Poly(Q)-Mediated Neurotoxicity by Restoration of Cellular Transcription Machinery. Mol Neurobiol. doi: 10.1007/s12035-018-1160-3. [Epub ahead of print]