Summary: New research uncovers molecular connections between aging and neurodegenerative disease risk.
Source: Harvard Medical School
Researchers have long sought to understand the causes of neurodegenerative diseases—conditions such as Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) that involve progressive loss of neurons and brain function. While genetics, infections and other factors can contribute, age remains the strongest risk factor for nearly all of these disorders. Recent work from Harvard Medical School sheds light on a specific molecular pathway that links aging to genetic risk for ALS and FTD.
Published in Cell on Aug. 23, the study identifies how interactions among three proteins—TBK1, RIPK1 and TAK1—connect genetic predisposition and aging to drive neurodegeneration. The findings point to possible therapeutic targets and underscore the importance of modeling aging in research on neurodegenerative diseases.
“This study provides the first description of a molecular event that connects aging with neurodegeneration,” said senior author Junying Yuan, the Elizabeth D. Hay Professor of Cell Biology at Harvard Medical School. “Understanding these interactions is a critical step toward explaining how aging increases vulnerability to neurodegenerative disease.”
TBK1, RIPK1 and TAK1: a molecular brake system
ALS, commonly called Lou Gehrig’s disease, causes progressive degeneration of motor neurons and is often fatal. FTD leads to early dementia and shares genetic and clinical overlap with ALS. About one in ten patients with ALS–FTD carry mutations that reduce function of the TBK1 protein. Previous research connected TBK1 with programmed cell death and neuroinflammation, but its precise role in disease onset and progression was unclear.
To model the partial TBK1 loss seen in patients, the researchers produced mice with only one functional copy of the TBK1 gene. These heterozygous mice appeared healthy, while complete loss of TBK1 (both copies) caused embryonic lethality. Importantly, the team discovered that deleting or blocking the activity of RIPK1—a protein that promotes cell death and inflammation—could fully rescue mice that otherwise lacked TBK1, allowing them to survive to adulthood. This showed that TBK1 normally restrains RIPK1 activity during development.
The team then examined TAK1, another regulator known to limit RIPK1. Analysis of human brain tissue revealed that TAK1 expression declines markedly with age, and TAK1 levels were even lower in brains of people with ALS compared with age-matched controls. This age-dependent drop in TAK1 suggested a mechanism linking aging to increased RIPK1 activity and neurodegeneration when TBK1 function is compromised.
Modeling age-related interactions drives disease features
To test how reduced TBK1 and TAK1 together might trigger disease, the researchers engineered mice with half the normal TBK1 and reduced TAK1 specifically in brain immune cells called microglia. These animals developed multiple hallmarks of ALS and FTD: motor deficits and hind-limb weakness, anxiety-like behavior in novel environments, neuronal loss, axonal degeneration, and biochemical changes associated with TDP-43 protein aggregation. Crucially, inhibiting RIPK1 in these mice reversed many of the symptoms.
Yuan and colleagues describe TAK1 and TBK1 as acting like two brakes on RIPK1. If one brake weakens, the other can compensate; but if both brakes fail—through genetic mutation and age-related protein decline—RIPK1 becomes overactive and promotes cell death and neuroinflammation. This model helps explain why people with TBK1 mutations typically develop disease later in life, when TAK1 levels naturally fall.
“Laboratory models often miss the aging element of disease,” Yuan said. “We need models that incorporate age as a critical factor if we want to better predict therapeutic responses in older patients.”
Implications for therapy and future research
Because RIPK1 promotes both cell death and neuroinflammation, it has become a therapeutic target. Several clinical trials are testing RIPK1 inhibitors in neurodegenerative and chronic inflammatory conditions. The new findings strengthen the rationale for those trials and suggest that blocking RIPK1 could counteract the combined effects of genetic risk and age-related decline in inhibitory pathways.
“The next few years should tell us whether RIPK1 inhibitors help patients with ALS and FTD,” Yuan said. “Our work increases confidence that targeting this pathway may be effective, particularly when age-related changes are taken into account.”
Despite many trials, effective disease-modifying therapies for neurodegenerative disorders remain elusive. This study highlights the need to include aging in experimental models so they better reflect disease processes in older humans. The researchers are now investigating why TAK1 levels fall with age and whether that decline contributes to other neurodegenerative diseases.
Additional authors on the study include Daichao Xu, Taijie Jin, Hong Zhu, Hongbo Chen, Dimitry Ofengeim, Chengyu Zou, Lauren Mifflin, Lifeng Pan, Palak Amin, Wanjin Li, Bing Shan, Masanori Gomi Naito, Huyan Meng, Ying Li, Heling Pan, Liviu Aron, Xian Adiconis, Joshua Z. Levin and Bruce A. Yankner.
Funding: The work was supported by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging and the National Institute of Mental Health of the U.S. National Institutes of Health (grant numbers 1R01NS082257, 1R01AG047231, RF1AG055521, RO1AG046174, RO1MH113279), as well as the National Key R&D Program of China, the National Natural Science Foundation of China and the Chinese Academy of Sciences.
Source: Kevin Jiang, Harvard Medical School. Publisher: Neuroscience News (organized).
Original research: “TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging.” Published in Cell, August 23, 2018. doi:10.1016/j.cell.2018.07.041
TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging
Aging is a major risk factor for both genetic and sporadic neurodegenerative disorders, yet how aging interacts with genetic predisposition to promote neurodegeneration is unclear. This study examines how partial loss of TBK1—a significant genetic cause of ALS and FTD comorbidity—leads to age-dependent neurodegeneration. TBK1 functions as an endogenous inhibitor of RIPK1, and embryonic lethality in TBK1-null mice depends on RIPK1 kinase activity. In aging human brains, TAK1, another endogenous inhibitor of RIPK1, shows a marked decline in expression. In mice with reduced TBK1, decreased myeloid TAK1 promotes key hallmarks of ALS/FTD—including neuroinflammation, TDP-43 aggregation, axonal degeneration, neuronal loss and behavioral deficits—all of which are prevented by inhibiting RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1 expression, which cooperates with genetic risk factors to drive ALS/FTD onset.