Synaptopathy Mechanisms in ALS Caused by C9orf72 Repeat Expansion

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disease caused by degeneration of motor neurons (MNs). ALS pathogenic features include accumulation of misfolded proteins, glutamate excitotoxicity, mitochondrial dysfunction at distal axon terminals, and neuronal cytoskeleton changes. Synergies between loss of C9orf72 functions and gain of function by toxic effects of repeat expansions also contribute to C9orf72-mediated pathogenesis. However, the impact of haploinsufficiency of C9orf72 on neurons and in synaptic functions requires further examination. As the motor neurons degenerate, the disease symptoms will lead to neurotransmission deficiencies in the brain, spinal cord, and neuromuscular junction. Altered neuronal excitability, synaptic morphological changes, and C9orf72 protein and DPR localization at the synapses, suggest a potential involvement of C9orf72 at synapses. In this review article, we provide a conceptual framework for assessing the putative involvement of C9orf72 as a synaptopathy, and we explore the underlying and common disease mechanisms with other neurodegenerative diseases. Finally, we reflect on the major challenges of understanding C9orf72-ALS as a synaptopathy focusing on integrating mitochondrial and neuronal cytoskeleton degeneration as biomarkers and potential targets to treat ALS neurodegeneration.

Investigation of Low Dose Cabazitaxel Potential as Microtubule Stabilizer in Experimental Model of Alzheimer's Disease: Restoring Neuronal Cytoskeleton

Background: Neuronal Microtubule (MT) tau protein, providing cytoskeleton to neuronal cells, plays a vital role, including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediated MT destabilization results in axonopathy, additionally neurotransmitter deficit and ultimately causing Alzheimer's disease. Pre-clinically, streptozotocin (3mg/kg, 10μl/ unilateral, ICV) stereotaxically mimics the behavioral and neurochemical alterations similar to Alzheimer's tau pathology resulting in MT assembly defects further lead to neuropathological cascades. Objective: Clinically approved medications such as Donepezil (DNP), rivastigmine, and Memantine (MEM) are responsible for symptomatic care only, but there is no specific pharmacological intervention that directly interacts with the neuronal microtubule destabilization. Methods: The current study focused on the involvement of anti-cancer agent microtubule stabilizer cabazitaxel at a low dose (0.5 and 2 mg/kg) alone and in combination with standard drugs DNP (5 mg/kg), MEM (10 mg/kg) and microtubule stabilizer Epothilone D (EpoD) (3 mg/kg) in the prevention of intracerebroventricular streptozotocin (ICV-STZ) intoxicated microtubule-associated tau protein hyperphosphorylation. Results: Chronic treatment of CBZ at a low dose alone and in combination with standard drugs showing no side effect and significantly improve the cognitive impairment, neurochemical alterations along with reducing the level of hyperphosphorylated tau by preventing the breakdown of the neuronal cytoskeleton, respectively. Conclusion: The above findings suggested that CBZ at low dose show neuroprotective effects against ICV-STZ induced microtubule-associated tau protein hyperphosphorylation in rats and may be an effective agent for the preventive treatment of AD.