Brain’s Immune System is Key to Recovery from Motor Neuron Degeneration in ALS Animal Model
Results in Penn study point to new approaches for ALS therapy
Article ID: 689831
Released: 20-Feb-2018 11:05 AM EST
Source Newsroom: Perelman School of Medicine at the University of Pennsylvania
First author Krista J. Spiller, PhD, a postdoctoral fellow, and senior author Virginia M-Y. Lee, PhD, director of the Center for Neurodegenerative Disease Research and a professor of Pathology and Laboratory Medicine, published their findings this week in Nature Neuroscience.
They found that microglia, the first and primary immune response cells in the brain and spinal cord, are essential for dealing with TDP-43-associated neuron death. This study is the first to demonstrate how healthy microglia respond to pathological TDP-43 in a living animal.
“The prevailing view in the field has been that immune system inflammation contributes to the death of neurons in ALS, but this study shows the opposite - that microglia are actually critical for neuronal survival,” Lee said.
The number of microglia cells remained stable in mice with ALS symptoms. However, after the researchers chemically suppressed expression of pathological human TDP-43 in the mice, microglia dramatically proliferated and changed their shape and what genes they expressed.
The researchers were perplexed as to why the microglia did not react automatically to the presence of mutant TDP-43 and how subduing its expression incited microglia to react. “This is still a mystery, but one that we’d very much like to figure out in future studies,” Spiller said.
The normally branched microglia retracted their extensions and expanded the size of their main cell bodies. (This rapid change in shape is fairly unique to microglia in the central nervous system, although macrophages, microglia’s immune-system counterpart in peripheral parts of the body, are similarly dynamic in their shape shifting.)
The now abundant, remade microglia multiplied by 70 percent after one week and selectively cleared accumulated human TDP-43 from motor neurons. Microglia surround TDP-43-filled neurons and turned on genes to make proteins that help them attach to the sick cells and induce a process called phagocytosis that envelops the mutant proteins for disposal. After the mop up, mice stopped exhibiting motor dysfunction symptoms such as leg clasping and tremors, and they regained their ability to walk and gain weight.
Conversely, TDP-43 was not fully cleared in mice with no microglia. When proliferation of microglia was blocked, the mice failed to regain full muscle function, revealing how important microglia are for cleaning up clumps of misfolded proteins.
“The way reactive microglia protect neurons points us towards new ideas for ALS therapies,” Spiller said. “For example, we want to know if we can encourage the expansion of microglia in early-stage ALS patients to save their motor neurons.”
This work was supported by the Judith and Jean Pape Adams Charitable Foundation, the ALS Association, the National Institutes of Health (PO1-017586), and gifts from the Koller and Pottruck families.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $405 million awarded in the 2017 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center — which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report — Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; Penn Wissahickon Hospice; and Pennsylvania Hospital – the nation’s first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine, and Princeton House Behavioral Health, a leading provider of highly skilled and compassionate behavioral healthcare.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2017, Penn Medicine provided $500 million to benefit our community.