I. Pioneering the discovery of neurotrophin receptor small molecule ligands.
Our team, also in collaboration with Dr. Stephen Massa at UCSF, has used in silico screening approaches to identify non-peptide, small molecules that mimic key domains of neurotrophin ligands and that modulate neurotrophin receptor function. Derivatives of these lead compounds are under further development.
Pioneering the development of the first small molecule neurotrophin receptor ligands derived from neurotrophin domains (JNS 2006)
Pioneering the development of the first small molecule TrkB ligands derived from BDNF domains (JCI 2010)
II. Elucidating signaling mechanisms of novel small molecule ligands.
Studies with primary neurons and other cell types demonstrate that neurotrophin small molecule ligands can trigger signaling mechanisms that are in some cases distinct from those stimulated by neurotrophins. These novel signaling patterns introduce promising opportunities for translational therapeutics.
Small molecule promotion of hippocampal neuron neurite outgrowth. Neurites degenerate in Alzheimer’s and other neurodegenerative disorders. (Longo Lab)
Small molecule activation of neurotrophin receptors in neurons destined to degenerate in Alzheimer’s disease. (Longo Lab)
Small molecules stimulate hippocampal stem cells to form newborn neurons. (Longo Lab)
Small molecules stimulate human stem cells to differentiate into tyrosine hydroxylase-positive neurons, the neuronal cell type that degenerates in Parkinson’s disease. (Longo Lab)
III. Application of small molecule ligands to neurological disorders.
Our laboratory team, along with our collaborators, is applying small molecules to in vivo models of Alzheimer’s and Huntington’s disease, Down’s syndrome, stroke, multiple sclerosis, Rett syndrome, spinal cord injury, epilepsy, age-associated cognitive loss and other neurological disorders. An NIH-funded U01 program is advancing selected compounds toward clinical trials.
Small molecule rescue of hippocampal dendrites. Dendrites degenerate in Alzheimer’s and other neurodegenerative disorders. (Longo Lab)
Small molecule rescue of synaptic spines. Synaptic spines mediate synaptic transmission and are among the most vulnerable structures in Alzheimer’s and other neurodegenerative disorders. (Longo Lab)
Intra-nuclear aggregates of huntingtin protein in the striatum of an R6/2 Huntington’s disease mouse. Small molecules hold promise for reducing Huntington’s degeneration (Longo Lab)