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Qian Cai
Qian Cai
Assistant Professor
(848) 445-1633
B231 Nelson Labs
Autophagy-Lysosomal Regulation in Neurodevelopment and Neurodegeneration


M.D., Shanghai Tonji University, School of Medicine, Shanghai, China
M.S., Shanghai Jiaotong University, School of Medicine, Shanghai, China,
Ph.D., National Institutes of Health (NIH)–Shanghai Second Medical University Joint Neuroscience Ph.D. program, Bethesda, MD

Postdoctoral training: Dr. Zu-Hang Sheng, advisor, NINDS, NIH, Bethesda, MD

Resident in Internal Medicine and Infectious Diseases, Shanghai Municipal Infectious Diseases Hospital, Shanghai, China
Resident in Infectious Diseases, Shanghai Rui-Jin Hospital, Shanghai, China
Research Fellow, Synaptic Function Section, NINDS, NIH, Bethesda, MD
Assistant Professor, Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ

Awards and Honors:

NIH Fellow Award for Research Excellence (2004)
The Outstanding Graduate Student Award, Shanghai, China (2006)
Exceptional Performance Award of US Federal Government Employees, NINDS, NIH (2006)
NIH Fellow Award for Research Excellence (2007)
NIH Fellow Award for Research Excellence (2008)
NIH Fellow Award for Research Excellence (2009)
NIH Pathway to Independence (PI) Award (K99/R00 award) (2009)
Charles & Johanna Busch Biomedical Award (2013)
Alzheimer’s Association NIRG Award (2014)
FASEB Science Research Conference Travel Award (2015)

Professional Memberships:
American Society for Cell Biology
American Society for Neuroscience
Associate Faculty Member of Faculty of 1000

Current Research

Autophagy-Lysosomal Regulation in Neurodevelopment and Neurodegeneration

Autophagy is a key homeostatic process whereby autophagosomes engulf damaged cytoplasmic components, protein aggregates, and dysfunctional organelles for lysosomal degradation. In neurons, autophagosomes are predominantly formed in distal axons and presynaptic terminals and undergo exclusively retrograde transport toward the soma where mature lysosomes are mainly located. The autophagy-lysosomal pathway is essential for the maintenance of neuronal homeostasis. Defects in this pathway have been implicated in a growing number of neurological disorders.

Mitochondria are essential organelles for neuronal function and survival. Dysfunctional mitochondria not only produce energy less efficiently, but also release harmful reactive oxygen species and initiate apoptotic signaling cascades, which have been linked to the pathogenesis of major neurodegenerative diseases including Alzheimer’s, Parkinson’s, Amyotrophic Lateral Sclerosis, and Huntington’s. Efficient elimination of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control in neurons.

The focus of our research is to elucidate the molecular and cellular mechanisms regulating the autophagy-lysosomal system and their impact on neuronal homeostasis in health and axonal degeneration. We are particularly interested in addressing the following questions: (1) What are the mechanisms regulating axonal transport, membrane trafficking, and autophagy-lysosomal function? (2) How is mitochondrial quality controlled through mitophagy in heathy and diseased neurons? (3) How is the endolysosomal system involved in the regulation of neuronal signaling? (4) How do defects in these mechanisms contribute to neurodegeneration? (5) What are the mechanisms regulating neuronal morphogenesis and synapse formation through the autophagy-lysosomal pathway?

Our study provides the evidence of dynamic and spatial Parkin-mediated mitophagy in elimination of defective mitochondria in live neurons. We reveal that inadequate mitophagy capacity contributes to mitochondrial defects in Alzheimer’s disease neurons. Our long-term goal is to elucidate the cellular mechanisms for proper turnover of damaged mitochondria and clearance of protein aggregates by enhancing autophagy-lysosomal function. We will evaluate if up-regulation of this system ameliorates neuropathology and attenuates behavioral abnormalities associated with major neurodegenerative diseases. The advance in our understanding of these mechanisms will provide a strong basis that could lead to the development of novel protective and therapeutic approaches.

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Our research article (Tammineni and Jeong et al., Human Molecular Genetics, 2017) is featured in the cover: (A) LAMP-1-labeled mature lysosomes loaded with active protease Cathepsin D (CathD) are mainly located in the soma, but are barely detected in MAP2-marked neuronal processes. (B) Snapin, a dynein motor adaptor, mediates the recruitment of dynein motors to late endosomes, thereby enabling their long-distance retrograde axonal transport. This process facilitates axonal retrograde trafficking of late endosome-associated retromer toward the soma, where retromer retrieves cation-independent mannose 6 phosphate receptors (CI-MPR) from the late endosome to the Golgi. Golgi-localized CI-MPR mediates trafficking and loading of critical proteases into lysosomes. Such a mechanism is essential for the maintenance of lysosome functional capacity in neurons.

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Our paper (Feng and Tammineni et al., Journal of Biology Chemistry, 2017) is selected as the representative for the Neurobiology category in “The Year in JBC: 2017”. The images from the paper are featured as part of the cover: fluorescence data and kymographs exploring the fate of the secretase BACE1, which initiates amyloid-? formation, during autophagy.

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Induction of Parkin-mediated mitophagy in mature cortical neurons. Upon mitophagy induction, Parkin translocates to depolarized mitochondria and accumulates in the somatodendritic regions of neurons. Arrows in enlarged views of the boxed somatodendritic area indicate Parkin ring-like structures surrounding fragmented mitochondria while an arrowhead marks a mitochondrion unlabeled by Parkin. Panels with enlarged views of a dendritic process showing mitochondria with no Parkin association at distal regions. (Cai et al., Current Biology, 2012)

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Activation of Parkin-mediated mitophagy in Alzheimer’s disease neurons. Parkin is recruited to depolarized mitochondria in Alzheimer’s disease neurons. Graph to the right is a line scan of relative DsRed-Mito and YFP-Parkin fluorescence intensities from an enlarged image in the somatic area of Alzheimer’s disease neuron (left panel). Mitophagy induction is coupled with altered mitochondrial motility in the axon of Alzheimer’s disease neurons. Vertical lines of kymograph images (lower panels) represent stationary organelles, oblique lines or curves to the right represent anterograde transport, and lines to the left indicate retrograde movement. (Ye et al., Human Molecular Genetics, 2015

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Autophagic stress at presynaptic terminals of neurons in Alzheimer’s disease mouse brains. Amphisome-like structures, indicated by arrows, accumulate at presynaptic terminals of Alzheimer’s disease neurons, which are not readily observed in the neurons from normal WT mice. (Tammineni and Ye et al., eLife, 2017)

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Mechanisms underlying autophagic stress in Alzheimer’s disease neurons. (A) In healthy neurons, autophagosomes are predominantly generated in distal axons. Through fusion with late endosomes (LEs) to form amphisomes, nascent autophagosomes gain long-distance retrograde motility by recruiting LE-loaded dynein-Snapin motor-adaptor transport machinery. Efficient retrograde transport rapidly moves amphisomes from distal axons to the soma where active lysosomes are relatively enriched. Such a mechanism enables neurons to facilitate cargo degradation within autolysosomes in the soma, thereby decreasing axonal stress. (B) In Alzheimer’s disease neurons, elevated cytoplasmic amyloid ? (A?) oligomers interact with dynein motors and competitively interfere with dynein-Snapin coupling. Such deficits disrupt recruitment of dynein motors onto Snapin-loaded LEs and/or amphisomes, and reduce their retrograde transport toward the soma for lysosomal clearance. As a result, amphisomes are trapped in distal axons and at presynaptic terminals, augmenting autophagic stress in Alzheimer’s disease neurons. (Tammineni and Cai, Autophagy, 2017)


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