research

Dr Mukherjee   MBBS, Ph.D  

Virginia Tech Carilion Research Institute 

This Research Project is headed by Professor Konark Mukherjee of Virginia Polytechnic Institute and State University who is researching a drug that may prevent cerebellar degeneration due to CASK loss and or generally may improve the quality of life of children suffering from the Cask Gene disorder  

To date research work from Dr. Mukherjee's laboratory suggests that CASK is not only critical for information transfer and processing in the brain, but it is also a key regulator of brain metabolism. Thus, a brain without proper CASK function cannot keep up with the normal rate of brain growth after birth.

10 April 2022

Dr Mukherjee   MBBS, Ph.D  

Virginia Tech Carilion Research Institute 

Development occurs at many levels, cells develop, organs develop and the individual develops. The brain is one of the fastest-growing organs in a child, at birth the weight of the brain is already a quarter of the adult size and by 6-7 years brain attains its adult size. According to Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), “neurodevelopmental disorders, are characterized by early-onset deficits of variable severity in personal, social, academic, or occupational functioning”. Thus the term neurodevelopmental disorder is a descriptor for a large variety of neurological conditions that arise early in an individual’s life, and does not provide a window into the possible mechanism of the disorder. Indeed a large number of neurodevelopmental disorders occur due to insult to the developing brain in a time-limited fashion such as infection (eg.Zika virus), toxins and drugs (eg. alcohol), or trauma (cerebral palsies). These insults are more likely to cause damage to the developing nervous tissue rather than alter the specific maturation process of neurons in the brain. Despite this knowledge, within neuroscience, neurodevelopmental disorders have often been seen through the prism of neuronal development, especially when such disorders are associated with specific genetic mutations.                 

 Mutations in CASK produce a neurodevelopmental disorder called microcephaly with pontine and cerebellar hypoplasia (MICPCH). It has been suggested that MICPCH may result either from improper migration of neurons to the right place during brain development or defects in synaptic neurotransmission. In the majority of MICPCH cases, however, there is no evidence of heterotopia which results from migrational defects in neurons. 

In the recently published study, we demonstrate that loss of CASK does not lead to alteration in early brain developmental trajectory. Rather, it produces loss of certain types of cells like cerebellar granule neurons. We also found that the functional loss that is seen in absence of CASK, occurs due to the loss of neurons and not due to defects in synaptic transmission. Finally, we found that in females, who have 2 CASK genes the neuronal loss is not progressive and stabilizes after early childhood. Our findings explain the clinical presentation of MICPCH in the population including the fact that microcephaly or developmental delay is often not detected for the first 3-6 months after birth and the disorder is often non-progressive. This study also indicates that an ability to stop neuronal death, especially in the first 5-6 years of life, when the brain is growing rapidly, may prove to be therapeutic.   

As referred to in my most recent Article ‘The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model published 28 March 2022’   “In some ways, that CASK-linked pathology is degenerative in nature provides a positive outlook. Because microcephaly in CASK-linked pathology progresses postnatally, there may be a temporal window when therapeutic intervention might prevent or slow further brain cell loss. Regression, even in adolescence, has also been observed in some cases of MICPCH [119], again offering the tantalizing possibility that a therapeutic approach might prevent such decline under conditions when degeneration is known to progress. The potential benefits of intervention might extend even further given that non-cell-autonomous toxicity could also affect functioning of the remaining neurons; reduction of such toxicity, especially when coupled with high-intensity rehabilitative measures [120], might offer real hope for a positive impact on functional outcomes.”  

https://www.mdpi.com/2073-4409/11/7/1131/htm

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