Cell Biology of Degeneration and Repair in the Nervous System: A preview of the ASCB Doorstep Meeting

Brain development, function, and degeneration are the central themes for the ASCB 2017 Doorstep Meeting, to be held on Saturday, December 2 in Philadelphia. The second annual Doorstep Meeting offers talks by experts from disciplines tackling the cell biology of the brain and gives ample time for speakers and attendees to engage. Frank Bradke, of the German Center for Neurodegenerative Diseases, and Kelsey C. Martin, of the University of California, Los Angeles, David Geffen School of Medicine, curated the meeting lineup.

Bradke and Martin have chosen researchers whose investigations of protein folding and intracellular trafficking have yielded insights into neurodegenerative diseases as well as researchers whose studies of brain development and brain disease have uncovered a central role for critical cell biological processes. Along with the talks, students and postdocs have the opportunity to present posters during one of two, hour-long poster sessions to be held during the morning and afternoon breaks of the Doorstep Meeting. (The deadline to submit an abstract for the Doorstep poster sessions is October 11. Acceptance is not guaranteed. Abstracts submitted for the 2017 ASCB|EMBO Meeting must be separately submitted to the Doorstep Meeting.)

The Doorstep Meeting talks include:

Development and Reprogramming of Neuronal Diversity in the Neocortex
Paola Arlotta, Harvard University
The Arlotta lab is elucidating the governing principles underlying developmental generation and postnatal maintenance of excitatory pyramidal neuron diversity in the cerebral cortex. Arlotta will describe how pyramidal neuron diversity impacts the behavior of other cell types during cortical development and discuss the critical effect on oligodendrocytes to guarantee generation of normal patterns of myelin distribution in different cortical layers.

Saving the Synapse: MHC Class I and Synapse Pruning during Development and in Alzheimer’s Disease
Carla Shatz, Stanford Bio-X, Stanford University
The Shatz lab has found that molecules previously thought to function only in immunity also act at neuronal synapses to regulate synapse pruning and plasticity in response to new experiences. Changes in the function of these molecules could contribute to developmental disorders such as schizophrenia and Alzheimer’s disease.

Gene Silencing Therapy for Neurodegenerative Disease
Don Cleveland, Ludwig Institute, University of California, San Diego
Cleveland will discuss how the combination of efforts using gene silencing with designer DNA drugs, adenoviral associated gene vectors, and genome editing mediated by site-specific nucleases could raise the possibility of development of effective disease-modifying therapies.

Dysfunction of Protein Translation in Neurodegeneration
Susan Ackerman,University of California, San Diego/HHMI
Forward genetics is used to identify genes responsible for phenotypes. Using this approach, the Ackerman lab has identified new mechanisms of neurodegeneration and has demonstrated that dysfunction of protein translation greatly impacts neuronal homeostasis in the aging mammalian brain.

Dynamic RNA-Protein Assemblies in Neurological Disease
J. Paul Taylor, St. Jude Children’s Research Hospital/HHMI
Mutations in several RNA-binding proteins (RBP) are linked to degenerative diseases, such as amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. The Taylor lab hypothesizes that a disturbance of phase transitions that alters the dynamic properties of membrane-less organelles could be the underlying reason for these diseases. Taylor will present evidence that mutations in RBPs alter the biophysical and material properties of these proteins in liquid assemblies and result in perturbed dynamics and functions of multiple membrane-less organelles.

Autophagy Dynamics in Neuronal Homeostasis and Neurodegeneration
Erika Holzbaur, University of Pennsylvania Perelman School of Medicine
Deficits in autophagic flux lead to the accumulation of protein aggregates and dysfunctional mitochondria and are characteristic of neurodegenerative diseases such as Parkinson’s, Huntington’s, and ALS. Holzbaur’s talk will feature live cell imaging of autophagy in neurons that reveals a dynamic pathway that is altered in both aging and disease.

Chaperone Functions in Protein Quality Control and Implications in Neurodegenerative Disease
F. Ulrich Hartl, Max Planck Institute of Biochemistry
Failure of the chaperone machinery to maintain proteostasis (the conformational integrity and balance of the cellular proteome) can result in protein misfolding–related diseases such as Parkinson’s, Huntington’s, and Alzheimer’s. Hartl will discuss recent findings from model systems suggesting that toxic protein aggregation in neurodegenerative disease is both a symptom and a cause of proteostasis decline.

Neuronal Mitostasis and Parkinson’s Disease
Thomas L. Schwarz, Boston Children’s Hospital and Harvard Medical School
Neurons last a lifetime, but proteins do not; proteins require constant turnover and synthesis.  For mitochondrial proteins this is particularly true, because the reactive oxygen species formed by the electron transport chain are prone to damaging mitochondrial proteins. This presentation will review what we know about the synthesis and degradation of mitochondria in the special context of neuronal architecture and the problems posed by having mitochondria up to a meter away from the nuclear DNA encoding their proteins. Particular attention will be given to the evidence that Parkinson’s can be a mitochondrial disorder and to the role of PINK1 as a trigger of the mitophagic clearance of damaged mitochondria.  PINK1 poses a particular problem for neurons because its normal halflife is just minutes; PINK1 mRNA transport on mitochondria and local translation can solve the problem of allowing a short-lived protein to support mitophagy throughout the axonal and dendritic arbors.

The Cell Biology of Protein Misfolding in Alzheimer’s and Parkinson’s Diseases
Dennis Selkoe, Harvard Medical School/Brigham & Women’s Hospital
For more than 30 years, the Selkoe lab has used human brain tissue, animal models, and living neurons to study in vitro characteristics and bioactivities of endogenous forms of amyloid β-protein, tau protein, and α-synculein in human neurodegeneration. Selkoe will talk about recent work in his lab that has implications for the initiation of diseases such as Parkinson’s and suggests potential disease prevention by compounds that stabilize physiological α-synuclein tetramers.