Immunotherapy targeting the C-terminal domain of TDP-43 decreases neuropathology and confers neuroprotection in mouse models of ALS/FTD.

Effective therapies are urgently needed to safely target TDP-43 pathology as it is closely associated with the onset and development of devastating diseases such as frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 pathology is present as a co-pathology in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Our approach is to develop a TDP-43-specific immunotherapy that exploits Fc gamma-mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP-43 function. Thus, using both in vitro mechanistic studies in conjunction with the rNLS8 and CamKIIa inoculation mouse models of TDP-43 proteinopathy, we identified the key targeting domain in TDP-43 to accomplish these therapeutic objectives. Targeting the C-terminal domain of TDP-43 but not the RNA recognition motifs (RRM) reduces TDP-43 pathology and avoids neuronal loss in vivo. We demonstrate that this rescue is dependent on Fc receptor-mediated immune complex uptake by microglia. Furthermore, monoclonal antibody (mAb) treatment enhances phagocytic capacity of ALS patient-derived microglia, providing a mechanism to restore the compromised phagocytic function in ALS and FTD patients. Importantly, these beneficial effects are achieved while preserving physiological TDP-43 activity. Our findings demonstrate that a mAb targeting the C-terminal domain of TDP-43 limits pathology and neurotoxicity, enabling clearance of misfolded TDP-43 through microglia engagement, and supporting the clinical strategy to target TDP-43 by immunotherapy. SIGNIFICANCE STATEMENT: TDP-43 pathology is associated with various devastating neurodegenerative disorders with high unmet medical needs such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Thus, safely and effectively targeting pathological TDP-43 represents a key paradigm for biotechnical research as currently there is little in clinical development. After years of research, we have determined that targeting the C-terminal domain of TDP-43 rescues multiple patho-mechanisms involved in disease progression in two animal models of FTD/ALS. In parallel, importantly, our studies establish that this approach does not alter the physiological functions of this ubiquitously expressed and indispensable protein. Together, our findings substantially contribute to the understanding of TDP-43 pathobiology and support the prioritization for clinical testing of immunotherapy approaches targeting TDP-43.

Influence of Body Mass Index, Handedness and Gender on Ruler Drop Method Reaction Time among Adults.

BACKGROUND: The interval between stimulus and response is called reaction time. It measures the sensorimotor function and performance of an individual. It involves stimulus processing, decision making and response programming. Many factors such as age, gender, handedness, physical fitness, sleep, fatigue, distraction, personality type and type of stimulus have been shown to affect reaction time. Thus the aim of this study was to assess the effect of body mass index, handedness and gender on reaction time. METHODS: A cross-sectional study was conducted in the Department of Physiology, Kathmandu University School of Medical Sciences, from October 2019 to December 2019, among 113 student volunteers. Height and weight were recorded and body mass index was then calculated. In ruler drop method, the students were made to sit with their forearm resting on a flat horizontal table surface, with their open hand at the edge of the surface. When the examiner suspended and released the ruler vertically the students were instructed to catch it as quickly as possible. RESULTS: Females had a faster reaction time than males when testing either hand (178.46±17.56 Vs 195.99±15.67; right hand) and (184.25±17.02 Vs 199.57±15.91; left hand). In females, right hand responded faster than left hand. In both gender, reaction time was faster in normal weight compared to overweight individuals but it was statistically insignificant. CONCLUSIONS: Females responded faster than males. Right hand had shorter reaction time than left hand in females. Reaction time was insignificantly prolonged in overweight individuals.