Axons require the axonal NAD-synthesizing enzyme NMNAT2 to survive. Injury or genetically induced depletion of NMNAT2 triggers axonal degeneration or defective axon growth. We have previously proposed that axonal NMNAT2 primarily promotes axon survival by maintaining low levels of its substrate NMN rather than generating NAD; however, this is still debated. NMN deamidase, a bacterial enzyme, sh...

Hereditary spastic paraplegia (HSP) is a neurological syndrome characterized by degeneration of central nervous system (CNS) axons. Mutated HSP proteins include myelin proteolipid protein (PLP) and axon-enriched proteins involved in mitochondrial function, smooth endoplasmic reticulum (SER) structure, and microtubule (MT) stability/function. We characterized axonal mitochondria, SER, and MTs in...

Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. ...

Aging constitutes the main risk factor for the development of neurodegenerative diseases. This represents a major health issue worldwide that is only expected to escalate due to the ever-increasing life expectancy of the population. Interestingly, axonal degeneration, which occurs at early stages of neurodegenerative disorders (ND) such as Alzheimer's disease, Amyotrophic lateral sclerosis, and...

Inflammatory demyelinating neuropathies such as Guillain-Barre syndrome (GBS) and its animal model, experimental autoimmune neuritis (EAN), are typically acute monophasic diseases of the PNS that can leave affected individuals with permanent disability due primarily to axonal degeneration. The mechanisms underlying the degeneration are not understood, but we have previously shown in vitro and i...

objective hereditary spastic paraplegia (hsp) is a degenerative disease of genetic origin affecting the corticospinal tracts in the spinal cord. there are three forms of inheritance: autosomal dominant hsp, autosomal rececive hsp and x-linked hsp. this disease is characterized by progressive spasticity of leg muscles with varying degrees of stiffness and weakness of other muscle groups. in this...

An emerging hypothesis in Parkinson's disease (PD) is that dopaminergic (DA) neurons degenerate through a " dying back " axonopathy wherein degeneration begins in the distal axon and progresses over time towards the cell body. Impaired axonal transport also appears to play an early, pivotal role in PD. Thus processes that delay axonal transport dysfunction and/or axonal degeneration might slow ...

Impaired axonal transport can contribute to axon degeneration and has been described in many neurodegenerative diseases. Multiple sclerosis (MS) is a common neuroinflammatory disease, which is characterized by progressive axon degeneration-whether, when, and how axonal transport is affected in this condition is unknown. Here we used in vivo two-photon imaging to directly assay transport of orga...

To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting...