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John Ravits, MD

Professor of Clinical Neurosciences
Department of Neurosciences

Contact Information
Phone: 858.246.1154

Location:Medical Teaching Facility (MTF), Room 153

Mailing address:
University of California San Diego
9500 Gilman Drive MC 0624
La Jolla, CA 92093-0624

Lab Website
Center for ALS Research and TherapyFaculty Profile Page

1. Neuroanatomic propagation:
My primary contribution to the ALS field has been to characterize, and model ALS as a disease that progresses neuro-anatomically as well as temporally. In a series of papers, I deconstructed ALS phenotypes to show that in addition to the well-appreciated involvement of motor neurons, important aspects of ALS biology are neuroanatomical: focality of the onset, random location, variably distribution between upper and lower motor neurons, and outward propagation. I predicted and showed the neuropathological correlate of this, namely loss of motor neurons as a function of distance from site of onset. I generated a hypothesis to model neuroanatomical propagation and showed applicability to familial ALS and to frontotemporal dementia (FTD), a related neurodegeneration. I have emphasized the role of contiguous or local spread, which is a distinct pattern of propagation from network spread, a theme also emerging in the literature. These ideas are helping formulate ideas about phenotypes, progression, neuropathology, mechanisms of cell-to-cell spread, regional therapies with stem cells, and biomarker identification.

2. Genomic profiling:
I exploited the propagating nature of ALS to identify locations of residual (undegenerated) motor neurons that did not but were at risk to succumb to the process of neurodegeneration based on anatomic location. I created a repository of human nervous systems with short post mortem intervals, laser captured residual motor neurons, profiled their transcriptome, and used innovative unbiased bioinformatics to identify novel pathways, especially enriched in extracellular matrix, transmembrane signaling and downregulation of microRNAs. Importantly, these identifications were made by an unbiased or discovery approach, and are distinctly different from pathways, such as axonal transport, apoptosis, RNA processing, protein clearance, or mitochondrial pathways. How far upstream or downstream these pathways are remains to be established.

3. ALS Neuropathology:
Consistent with my interest in neuroanatomical propagation of ALS, I am studying the post-mortem ALS CNS neuropathologically. I have created a tissue repositories from patients whose phenotypes have been well-characterized and am studying the anatomy of key neuropathological features. In this, I am seeking to characterize the distribution of changes between brain and spinal cord, comparing neuronal pathology in Betz cells of layer 5b of motor cortex and in alpha motor neurons in lamina IX of anterior horns, and the spread of pathology based on somatotopic anatomy within these regions. Related to this, I am studying mechanisms of neuronal death, such as by the RIPK1-mediated necroptosis. RIPK1 is a key mediator of the innate immune response that regulates both inflammation and cell death.

4. CORF72 ALS:
I am working on identifying mechanisms and therapeutic targets of neuronal degenerations in ALS caused by repeat expansion mutations in C9orf72. There is strong evidence for gain-of-function either at the RNA or protein levels from both the sense and antisense directions. Our work (and that of others in the field) has shown a significant presence of transcripts from the antisense strand as well as the sense strand, essentially doubling the number of candidates for therapeutic targeting. My current research is trying to compare the relative contributions of these oppositely directed transcripts to pathogenesis in a mouse model and in humans neuropathology and trying to ascertain the most appropriate target for antisense oligonucleotide (ASO) therapies. ASOs are exquisitely engineered gene therapies and have the potential to create a true revolution in neurotherapeutics. C9forf72-ALS/FTD, which is as much as 8% of ALS and FTD patients, will be a critical testing ground. Related to this, my translational research group is participating in the international effort to develop ASOs for ALS by intrathecal delivery, beginning with mutSOD1-associated ALS.

1. Neuroanatomic propagation:
1. Ravits J, et al. Neurology. 2007 May 8;68(19):1571-5. PubMed PMID: 17485643.
2. Ravits J, et al. Neurology. 2007 May 8;68(19):1576-82. PubMed PMID: 17485644.
3. Ravits JM and La Spada AR. Neurology. 2009 Sep 8;73(10):805-11. PubMed PMID: 19738176.
4. Ravits J. Exp Neurol. 2014 Dec;262 Pt B:121-6. PubMed PMID: 25108067.

2. Genomic profiling:
1. Rabin SJ, et al. Hum Mol Genet. 2010 Jan 15;19(2):313-28. PubMed PMID: 19864493.
2. Emde A,et al. EMBO J. 2015 Nov 3;34(21):2633-51. PubMed PMID: 26330466.

3. ALS Neuropathology:
1. Bodansky A et al. Amyotroph Lateral Scler. 2010 May 3;11(3):321-7. PubMed PMID: 20225928.
2. Song F, et al. Amyotroph Lateral Scler Frontotemporal Degener. 2014 Mar;15(1-2):77-83. PubMed PMID: 24229388.
3. Ito Y, et al. Science. 2016 Aug 5;353(6299):603-8. PubMed PMID: 27493188.
4. Braak H et al. Acta Neuropathologica. 2017 Jan;133(1):79-90. PMID:27757524
5. Da Cruz S et al. Acta Neuropathological. 2017 Feb 28. PMID:28247063

4. CORF72 ALS:
1. *Lagier-Tourenne C, *Baughn M, et al. Proc Natl Acad Sci U S A. 2013 Nov 19;110(47):E4530-9. PubMed PMID: 24170860.
2. Sareen D, et al. Sci Transl Med. 2013 Oct 23;5(208):208ra149. PubMed PMID: 24154603.
3. Jiang J, et al Neuron. 2016 May 4;90(3):535-50. PubMed PMID: 27112497.