Research Program 1: The pathogenic mechanisms of ALS-related genetic mutations in the function and survival of motor neurons  First described in the nineteenth century by Jean-Martin Charcot, ALS is now recognized as the most common degenerative disorder of motor neurons.  ALS lies within a spectrum of heterogeneous syndromes that lead to the selective degeneration of corticospinal and spinal motor neurons.  Mutations in the abundant free radical scavenging enzyme superoxide dismutase 1 (SOD1) have been the focus point of ALS research in the past decade.  Recently, several other causative genes for ALS and related motor neuron diseases (MNDs) have been identified, including ALS2, ALS4, dynactin p150^glued, VAPB, TDP-43, FUS, and VCP.  These newly identified genetic mutations provide rich resources to explore potential novel and common pathogenic mechanisms of ALS and related MNDs.  Currently, our ALS research mainly focuses on a missense mutation (P56S) of vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB), which has been recently identified as the genetic cause of ALS8, a slowly progressive and late-onset dominant form of ALS.

Research Program 2:  Function and pathogenic mechanisms of a-synuclein, and LRRK2 in Parkinson’s disease  Parkinson disease (PD) is the most common degenerative movement disorder initially described by Dr. James Parkinson in nineteen century.  The clinical symptoms of PD can include classical extrapyramidal signs such as resting tremor, rigidity, akinesia/bradykinesia, and postural instability, with psychiatric and cognitive presentations appearing in some patients.  The cardinal neuropathological hallmarks of PD are the relatively selective degeneration of midbrain dopaminergic (mDA) neurons and the presence of abnormal intracellular deposits of protein aggregates largely composed of ubiquitin and α-synuclein (a-syn) known as Lewy bodies (LBs) and Lewy neurites (LNs).  Two dominantly inherited and four recessively inherited genetic mutations have been shown to unambiguously cause PD in multiple families spanning a wide range of geographical regions of the world.  Most of these monogenic forms, with the exception of leucine-rich repeat kinase 2 (LRRK2) mutations, are rarely found in classical late-onset sporadic PD, and in sum, account for nearly 10% of all PD cases.  The monogenic forms also appear to differ with respect to neuropathology.  While patients with dominant genetic alterations in α-syn and LRRK2 typically have idiopathic PD pathology such as LB, LN, and DA cell loss, patients with recessive mutations typically lack LB pathology.  Our current PD programs mainly focus on the pathogenic mechanisms of PD-related dominant mutations in α-syn and LRRK2.

Research Project 3: Pathogenic mechanisms of Dynactin p150^glued in Perry syndrome and motor neuron diseases  The dynein/dynactin complex is critical in an array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis.  P150^glued, the largest subunit of dynactin complex mediate the association of dynein/dynactin complex with microtubules.  A missense mutation (G59S) at the conserved CAP-Gly (cytoskeleton-associated protein, glycine-rich) domain of p150^glued protein is linked to a slowly progressive, autosomal dominant form of lower MND without sensory symptoms.  Recently, three more missense mutations (G71A, G71R, and Q74P) at the same CAP-Gly domain of dynactin p150^glued are identified as the cause of Perry syndrome, a type of PD with severe mental depression and central hypoventilation.  It is very intriguing to imagine how the MND and Perry mutations within the same CAP-Gly domain of p150^glued cause a rather selective loss of spinal motor neurons or mDA neurons.  Therefore, we are interested in delineating the pathogenic properties of MND-related G59S and Perry syndrome-related G71R missense mutations in the CAP-Gly domain of p150^glued protein.