A Novel approach to therapy in ALS and ALS/Dementia using new insights from ALS5/SPG11

  • Siddique, Teepu (PD/PI)
  • Deng, Han-Xiang (Co-Investigator)
  • Lukas, Thomas John (Co-Investigator)

Project: Research project

Project Details


Truncation mutations in SPG11 are associated with juvenile onset amyotrophic lateral sclerosis (ALS5), spastic paraplegia and other neurodegenerative conditions. We recently identified a novel pathology of aggregation of large dense core vesicles (LDCVs) in the motor neurons of a patient with a juvenile form of ALS and dementia called ALS5/SPG11. We have now verified such pathological aggregation of LDCVs also in our knock out (KO) mouse model of Spg11. We also have evidence that LDCV trafficking is impaired by mutations in the spastic paraplegia gene SPG11 which encodes a large protein called spatacsin that is a component of LDCVs. LDCVs pathology in motor neuron degeneration provides a new venue to develop novel therapies. We hypothesize that the LDCVs sequester in the soma and the cargo are constrained to perform their presumed neurotrophic and/or functions or communication functions. LDCVs are known to carry neuropeptides such as substance P, neuropeptide Y, brain-derived neurotrophins (e.g. BDNF), calcitonin gene related peptide (CGRP) and chromogranins. Release of LDCV cargo is regulated; they must be regenerated in the neuronal soma and refilled. The complete cargo of the motor neuron LDCVs has not been established. Studies of motor neuron LDCV cargo may reveal a novel peptide or neurotransmitter/neuromodulator whose significance may have been overlooked in motor neuron biology and which may broadly prevent or treat motor neuron degeneration. The pathological sequestration of LDCVs in aggregations in the soma of motor neurons suggests such a mechanism. A broader application of our research may be relevant because Chromogranin A, one of the markers by which LDCVs are recognized, is present in the pathological inclusions of spinal motor neurons in the sporadic form of human ALS. The abundant material available from our Spg11 KO mouse model and iPSCs derived motor neurons from eleven ALS5/SPG11 patients provides us a rare opportunity to satisfactorily carry out the proposed experiments in a robust and reproducible manner with techniques currently in use in our laboratory.This project is directed towards the neuron specific identification of the protein components and peptide cargo within large dense core vesicles (LDCVs) obtained from the Spg11 knock-out mouse and human (ALS5/SPG11 patients) induced pluripotent stem cell-derived neurons. In addition, we will identify molecularly proximate binding partners with the use of an engineered hybrid protein consisting of a modified biotin ligase bound to spatacsin and compare with the LDCVs cargo inventory from motor neuron or those derived from other neuronal systems of the Spg11 KO mouse. Motor neurons derived from human SPG11/ALS iPSCs will be evaluated for LDCVs aggregation, soma morphology, neurite extension and branching and cell viability. Suitable candidate cargo molecules will be tested for positive effect on these parameters of iPSC derived motor neurons. Knowledge of the cargo from neurons in specific regions of the brain may enable replacement therapies that deliver specific cargo (e.g. neuropeptides) to affected areas of the CNS and thus restore neuronal homeostasis.This exercise should provide a new inventory of therapeutics for ALS, ALS/dementia and possibly other forms of neurodegeneration.
Effective start/end date9/1/188/31/21


  • National Institute of Neurological Disorders and Stroke (5R21NS109917-02)


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