The Mechanisms Behind Neurodegenerative Diseases: New Insights on Alzheimer’s, Parkinson’s, and ALS

As the life spans of some people keep inching upward, neurons may struggle to keep up. Unlike other cells in the body, which experience fairly regular turnaround, neurons are largely irreplaceable—and therefore most must function optimally for nearly a century. The consequences of dysfunction are devastating: neurodegenerative diseases like Alzheimer’s, amyotrophic lateral sclerosis (ALS), Parkinson’s, or Huntington’s take a significant physical, emotional, and economic toll on individuals, health care systems, and society.

Both age-related and early-onset neurodegenerative diseases are pressing contemporary health issues. Researchers at Yale School of Medicine are diving into the underlying mechanisms of these diseases—pinpointing genetic causes, identifying faulty regulatory pathways, and developing novel biomarkers—to transform our understanding of what goes wrong and translate these findings into treatment avenues.

Many neurodegenerative diseases are characterized by proteins that fold incorrectly and then pile up as aggregates in the brain, but several converging factors can produce this pathological phenotype. Investigators at Yale have implicated genetic mutations, faulty protein quality controls, and dysfunctional cellular cleaning machinery as mechanisms of disease.

Janghoo Lim, PhD, associate professor of genetics and neuroscience, is interested in understanding how erroneous repeats within the genetic code can cause degeneration. Perhaps the most familiar example is the repeating nucleotide triplet CAG, which causes the polyglutamine buildup in Huntington’s disease. Lim studies two additional polyglutamine diseases: spinocerebellar ataxia type 1 (SCA1) and spinal and bulbar muscular atrophy (SBMA), which most severely target the cerebellum and the spinal cord respectively. Understanding the causes and effects of these disorders entails asking why specific subregions of the brain are more sensitive to degeneration than others.

Lim and his colleagues have employed a variety of investigative techniques, including genetics and computational neuroscience, to trace transcriptional changes on the cellular level. In doing so, they’ve generated longitudinal data about molecules and pathways that are altered throughout the life of an individual cell in the brain, and how different populations of cells are involved in various aspects of disease. They hope that these data will allow them to predict a cell’s trajectory and identify ways to intervene when it begins to teeter off-course.

Other repeat expansion diseases are less well understood: Junjie Guo, PhD, assistant professor of neuroscience, said that about half of all inherited cases of ALS and frontotemporal dementia involve a repeating six-nucleotide sequence that causes both RNA and protein aggregation in neurons, but the exact pathological mechanism is unclear. These mutations are unusual in that the repeating sequences are found within the intron—a noncoding region of the gene—but they are still translated into polypeptides. “There are a lot of reasons to think that this method of translation is relevant to pathogenesis,” Guo said.

He also wonders how these introns had eluded cellular RNA quality control processes. Healthy cells have a mechanism called nonsense-mediated mRNA decay, which should detect and degrade mutated RNA before it can accumulate. “It turns out that the polypeptides produced by RNA repeats can cripple this quality control process in neurons, which further accelerates the accumulation of deleterious RNA,” Guo said. “We’re hoping that we can slow down the progression of the disease by restoring the RNA quality.”

Shawn Ferguson, PhD, associate professor of cell biology and of neuroscience, has taken a different approach to understanding the consequences of these mutations. What if the problem isn’t just that there’s a buildup of misfolded proteins, he asks, but rather that the cell is unable to dispose of them once they’ve aggregated?

Ferguson’s lab studies lysosomes, the organelles tasked with degrading macromolecules to clear cellular waste and recycle nutrients. Lysosomes are particularly crucial in neurons, given the longevity expected of the cells. Moreover, the extreme size of neurons also presents challenges as these cells must also ensure that lysosomes are properly distributed over long distances. Genes encoding lysosomal pathway proteins have been flagged as risk factors for inherited neurodegenerative diseases, but the pathological impact—consistent with other conditions associated with aging—is incremental. “We’re looking at the long-term consequences of relatively subtle defects,” Ferguson said.

One of his current projects focuses on Alzheimer’s disease. Ferguson noted that electron microscope images show clusters of swollen neuronal axons near amyloid plaques, a hallmark of Alzheimer’s disease brain pathology. “These axons are absolutely packed with lysosomes,” Ferguson said. “This stood out to me because healthy axons have very few lysosomes. Lysosomes are usually very efficiently transported out of axons, and this is critical for their ability to acquire the enzymes that allow them to degrade toxic protein aggregates. I therefore wondered whether this unusual distribution was relevant to the disease.”

Using a mouse model, Ferguson and his colleagues determined that impaired lysosome transport within axons resulted in dramatically worsened amyloid plaque pathology—demonstrating that dysfunctional lysosomes are contributing to Alzheimer’s disease. Ferguson believes that the coordinated processes of lysosome biogenesis and transport are disrupted; the ensuing abnormal axonal lysosome accumulations may become sites where the amyloid precursor protein (encoded by a gene tightly linked to Alzheimer’s disease risk) is cleaved to form the amyloid peptide that can aggregate and cause disease.

Ferguson hopes that the research will reveal ways to restore lysosome transport and function. “Understanding how lysosomes are transported in axons to meet the extreme demands of neurons can help us develop strategies to enhance this process for the treatment and prevention of Alzheimer’s disease,” said Ferguson.

Synapses—the spaces between neurons where neurotransmitters are released from one cell to elicit signals in a neighboring cell—are crucial to brain function. In many neurodegenerative diseases, synaptic function is impaired.

Stephen Strittmatter, MD, PhD, the Vincent Coates Professor of Neurology and professor of neuroscience; the director of Cellular Neuroscience, Neurodegeneration and Repair; the director of the Yale Alzheimer’s Disease Research Center; and the director of the Yale Memory Disorders Clinic, seeks to curb this process by blocking the pathways that trigger protein buildup at the synapse. When amyloid beta begins to accumulate in the brain, it interacts with prion protein—a molecule also implicated in Creutzfeldt-Jakob disease (CJD), a rare but fatal neurodegenerative condition.

The amyloid association induces a signaling cascade in which another protein, metabotropic glutamate receptor 5 (mGluR5), recruits inflammatory mediators and tau protein to the synapse. This aggregation hinders neurotransmission between cells and eventually contributes to the loss of synapses and cell death. “By blocking this molecular pathway with drugs, we can preserve synapses and protect function, even when there is inflammation or when amyloid and tau proteins are piling up in the brain,” Strittmatter said.

So far, Strittmatter’s team has developed multiple pharmacological methods of targeting prion protein and mGluR5. In mice that had aged and developed deficits analogous to those seen in Alzheimer’s patients, these drugs protected neurons and allowed them to slowly rebuild synapses, eventually restoring learning and memory function. Importantly, these therapies worked even after synapse damage had induced cognitive defects—a promising finding, given that the amyloid begins piling up as much as 10 years before people begin developing symptoms of Alzheimer’s. Measures to prevent the buildup of aggregates themselves often come too late.

“The window we’re looking at in the mouse model is most similar to mild Alzheimer’s, where progressive synapse loss causes symptoms. At this stage in humans, very few neurons have died, but there is already the accumulation of amyloid in the brain and the beginning of tau accumulation,” Strittmatter said. “Because we’re using these drugs to protect synapses from aggregated damaging protein, it ‘resets the clock,’ allowing the brain to recover somewhat.”

Strittmatter has measured synaptic density in these mouse brains by collaborating with Christopher van Dyck, MD, professor of psychiatry, neurology, and neuroscience; director, Alzheimer’s Disease Research Unit, Yale Alzheimer’s Disease Research Center; and director of the Division of Aging and Geriatric Psychiatry; as well as Richard Carson, PhD, professor of radiology and biomedical imaging and of biomedical engineering, and director of the Yale PET Center, which uses positron emission tomography (PET) imaging to map brain activity.

Carson, van Dyck, and their colleagues have developed and applied a synaptic PET ligand—the first of its kind—which can quantify synaptic loss or regrowth in Alzheimer’s disease. The opportunity to use a stable biomarker to examine the brains of living patients is exciting because memory tests—a longtime research tool for evaluating therapies—produce notoriously noisy data, and examining brain tissue during an autopsy will typically depict only the disease’s latest stages. Van Dyck hopes that the tracer will be used to screen drugs to determine whether they’re worth pursuing further.

“Synapse concentration has widely been touted as the pathologic feature that correlates best with cognitive performance in Alzheimer’s disease,” van Dyck said. “If we are able to validly measure synapse concentrations in living people, then there are enormous implications for therapeutic trials.” Van Dyck’s lab received a grant to fund the researchers’ investigation into synaptic PET imaging of presymptomatic individuals who fall into such high-risk categories as first-degree relatives of Alzheimer’s patients or people with known genetic markers for the disease. “We already know that we can see amyloid buildup as early as 20 years before the onset of symptoms, but this would be the first time we could measure actual synapse loss,” van Dyck said.

Pietro de Camilli, MD, the John Klingenstein Professor of Neuroscience and professor of cell biology; a Howard Hughes Medical Institute investigator; chair of the Department of Neuroscience; and director of the Kavli Institute for Neuroscience and the Yale Program in Cellular Neuroscience, Neurodegeneration and Repair, is a researcher who also examines synapses through the lens of a neuroscientist and a cell biologist.

The main focus of his lab is synaptic vesicles: the small sacs that store neurotransmitters and release them into the extracellular space by fusing with the limiting membrane of the cell. After the neurotransmitters have been released, the lipid membranes of these sacs are rapidly recaptured from the outer membrane of the cell and reutilized for the generation of new neurotransmitter-filled vesicles. This recycling process is orchestrated by intracellular proteins (coat proteins) that are recruited to the surface of the sacs and then shed from them in a precise temporal sequence.

One protein that the De Camilli Lab had discovered is called synaptojanin 1. It is a lipid-modifying enzyme that participates in this process. “This protein helps take apart the coat so that this vesicle recycling process can proceed to the next step,” de Camilli said. “If this uncoating does not occur, you’ll see an accumulation of coated vesicles, which disrupts the cycle and impairs neurotransmission.”

Genetic sequencing of patients with familial early-onset Parkinson’s disease revealed that in rare families, this condition is the result of a mutation in the SYNJ1 gene that encodes synaptojanin 1. Interestingly, mutations in the DNAJC6 gene that encodes auxilin, another protein that cooperates with synaptojanin 1 in the uncoating of reforming synaptic vesicles, also results in early-onset Parkinson’s disease—further strengthening the notion of a link between synaptojanin 1’s function and this neurodegenerative condition.

De Camilli and co-workers now hope to understand more about synaptojanin itself and its physiological function. They introduced the patients’ mutation into the mouse genome and showed the occurrence of Parkinson-like defects in these mice. Interestingly, the levels of several other Parkinson’s disease-linked proteins (including auxilin) are altered in the brains of these mice, confirming that synaptojanin 1 lies at the core of a protein network whose dysfunction leads to the disease.

Building on these findings, they have now expanded the scope of their research to other Parkinson’s disease-linked genes. They hope that these studies will contribute information that ultimately leads to the identification of targets for pharmacological interventions aimed at arresting or slowing the course of the disease.

Grappling with the complexities of neurodegenerative disease requires patience, creativity, and a willingness to consider new perspectives. These researchers’ work is a testament to Yale’s fostering of interdisciplinary partnerships in which cell biologists, geneticists, basic neuroscientists, and clinicians cooperate to answer fundamental questions about disease and consider therapeutic innovations. “A unique feature of Yale research on neurodegeneration is that it is anchored within a very strong cell biology community,” said de Camilli.

These efforts have led to initiatives like the Program in Cellular Neuroscience, Neurodegeneration and Repair, with broad research support provided from within the Kavli Institute for Neuroscience. “It’s been exciting to see Yale’s growing commitment to neurodegenerative disease research on many levels, especially in basic science that complements clinical research,” van Dyck said.

“Yale is a great place for multidisciplinary investigations,” said Strittmatter. “We have a launch pad to bring many labs together. I think we’re well positioned to make a difference by approaching neurodegeneration and repair from multiple perspectives, taking genetic and pathologic data, designing therapeutics, and ultimately making a clinical impact.”

Originally published Spring 2020; updated May 10, 2022