Abstract Details

Title Meta-analysis of Genetic Expression Profiles in Amyotrophic Lateral Sclerosis

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P4 - Poster Session 4 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-004

Objective Demonstrate the utility of our meta-analysis platform to elucidate pathogenesis of amyotrophic lateral sclerosis (ALS).

Background ALS is a fatal, incurable neuromuscular condition which has a multifactorial etiology that likely includes genetic, environmental and other factors. Treatment for ALS is largely symptomatic with available disease specific therapies only modestly slowing progression. Elucidating ALS pathogenesis is necessary to establish more robust biomarkers and effective therapies.

Design/Methods The National Center for Biotechnology Information Gene Expression Omnibus (GEO) is an open database of more than 2 million samples of functional genomics experiments. The Search Tag Analyze Resource for GEO (STARGEO) platform allows for meta-analysis of genomic signatures of disease and tissue through tagging of individual samples across different studies. We analyzed 81 motor neuron biopsy specimens from ALS patients against 53 healthy control samples, and we then analyzed the meta-data using Ingenuity Pathway Analysis.

Results Motor neuron sample analysis revealed complement activation, dendritic cell maturation and Th1/2 cell activation as pathways involved in ALS. TGF-β1 and interferon-γ were top upstream regulators. We observed marked upregulation of several functionally described genes, including alpha 1-antichymotrypsin (SERPINA3), chitinase-1 (CHI3L1), and aquaporin 4 (AQP4).

Conclusions Our analysis supports characteristics of ALS pathogenesis such as neuro-inflammation, immune system dysregulation, and disruption of the blood-brain-barrier (BBB). Upregulation of SERPINA3, an acute phase reactant, may be the result of aberrant pro-inflammatory signaling mediated by interferon-γ. Complement activation may also play a downstream role. High levels of CHI3L1 are also indicative of microglial-mediated neuro-inflammation. TGFβ1 overexpression likely contributes to atypical immune regulation of T-cells and interferes with the neuroprotective function of microglia. Lastly, overexpression of AQP4, which has been observed in ALS rodent models, can be linked to BBB disruption, glutamate transporter expression levels and interstitial clearance of ALS-pathogenic protein deposits such as the well-described SOD1 mutant protein.

Authors/Disclosures
Samuel A. Frank, MD, FAAN (Beth Israel Deaconess Medical Center/Harvard Medical School) PRESENTER	Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for uniQure. Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva. Dr. Frank has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. The institution of Dr. Frank has received research support from Huntington's Disease Society of America. The institution of Dr. Frank has received research support from Roche/Genentech. The institution of Dr. Frank has received research support from CHDI Foundation. The institution of Dr. Frank has received research support from Huntington Study Group. The institution of Dr. Frank has received research support from Cerevel.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Adam Quick, MD (The Ohio State University)	The institution of Dr. Quick has received research support from NINDS. The institution of Dr. Quick has received research support from NEALS.

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