The build-up of misfolded and toxic protein aggregates is associated with multiple disease conditions. Efficient protein quality control machinery is required to maintain homeostasis and good health. Nazir laboratory at CSIR-CDRI aims to understand mechanistic aspects related to the accrual of malformed and unwanted protein aggregates that hamper functioning of, and communication between, neurons. The larger aim being identification of protein targets, epigenetic interventions and functional processes, that can aid in efficient clearance of noxious build-ups while eliciting positive effects on other key factors including neuroprotection, neuronal repair and functional outcome related to age associated neurodegenerative diseases.

The increasing size of ageing population poses a challenge of dealing with age associated diseases so that the quality of healthy life, within the elderly, does not deteriorate. Worldwide statistics of age associated neurodegenerative diseases are alarming with United States expecting 14 Million of its elderly to be afflicted with Alzheimer’s disease by year 2050 costing the nation about $1.1 Trillion annually . Presently 5.8 million Americans are diagnosed to have AD costing the country $290 Billion in 2019 alone. In India, more than 4 million elderly are living with Alzheimer’s and other forms of dementia giving the country third highest load of such patients after China and USA. The resulting burden is not only in terms of funds spent or work days lost, but most importantly in terms of the distressing quality of life of patients and care givers. The major hurdle in the way of finding a complete cure for neurodegenerative diseases, is their multi-factorial nature. These diseases present with molecular malfunctions ranging from, aggregation of misfolded proteins, excessive oxidative stress and decreased neurotransmitter availability; to cellular effects like engulfment of cellular organelles or complete death of specific brain cells, thus rendering patients debilitated and frail.

Neurogenesis, Neuroprotection and Neuronal Repair: Considering the increasing impact of neurological disorders particularly on our ageing populations, understanding the processes of neuronal health and death, has become most pertinent than ever. We know that neurons die in patients afflicted with neurodegenerative diseases thus leading to debilitating conditions including dementia, motor disorders and declined mental health; what we don’t know is how to cure these conditions fully. On one hand, these diseases are posing challenges to medical professionals as well as scientists, but on the other hand the growing amount of data from advanced research and access to newer techniques, provides with an opportunity to carry out in-depth studies on the subject. The circuitry and networking of neurons which is central to their physiological outcome, offers interesting clues in light of research efforts from past decade that has now established the importance of adult neurogenesis in the context of healthy brain function. The neuro-architecture of brain, not only consists of neurons, but is provided with its developmental paradigm via the network of glial cells as well. It is known that after generation, neurons lose the mitotic nature of cell division whereas glial cells retain it. Evidence exists that glia act as neural progenitors and facilitators of synaptic plasticity as glia can regulate neuronal development and physiology.

Nazir laboratory employs C. elegans model, that exhibits immense advantages in terms of studying neuronal as well as glial cells with profound ease of carrying out genetic manipulations towards identifying critical genetic and proteomic events providing key to understand whether it could be possible to counter neuronal death via reprogramming glial cells to either trigger neurogenesis or to reprogram themselves as neurons. More specifically, the laboratory aims at studying evolutionarily conserved transcription factors that guide embryonic neurogenesis and axon development. What makes the studies on C. elegans glial cells interesting is the fact that it expresses specific markers in the 56 glial cells (yes, the number of cells is that precise!) and thus brings forth the intriguing subject of correlation between glial cells, neurogenesis and possibility of cellular reprogramming under the conditions of proteotoxic stress in ageing nervous system, which the laboratory is delving deeper into. The laboratory makes use of genetic and pharmacological interventions including RNAi induced gene silencing, transgene constructs (GFP/YFP), Transcriptome analysis, micro RNA expression studies and associated aspects related to protein aggregation, cellular signaling and neuronal cell death, towards understanding mechanistic aspects related to human Alzheimer’s and Parkinson’s disease. The laboratory is equipped with state-of-the-art facilities including high end C. elegans workstations with Stereozoom microscopes and imaging tools, C. elegans culture room equipped with customised sterile cabinets, Bacterial culture facility with Class II Biosafety cabinet, Automated fluorescence microscope with imaging system, Genetic microinjection system for C. elegans, PCR, Real time PCR, Multimode plate reader with Fluorescence/Luminescence/Absorbance suites, Electrophoresis/Blotting facility and all necessary infrastructural setup required for carrying out cloning, expression and transgenesis related studies. The lab is also maintaining a repository of 90+ transgenic and knockout mutant strains of C. elegans and an RNAi library of ~17,000 bacterial clones required for silencing 85% of the genome of C. elegans. The laboratory also has access to institutional Confocal microscopy, Multi-photon microscopy, NextGen sequencing (Ilumina MiSeq), Microarray, 2D DIGE and multiple other facilities that are required for addressing the specific aims of the studies.