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Spinocerebellar ataxia 4 is a devastating progressive movement disease that can begin as early as the late teens. Now, a multinational research team has conclusively identified the genetic difference that causes the disease, bringing answers to families and opening the door to future treatments. Spinocerebellar ataxia 4 is a devastating progressive movement disease that can begin as early as the late teens. Now, a multinational research team led by University of Utah researchers has conclusively identified the genetic difference that causes the disease, bringing answers to families and opening the door to future treatments. Some families call it a trial of faith. Others just call it a curse. The progressive neurological disease known as spinocerebellar ataxia 4 (SCA4) is a rare condition, but its effects on patients and their families can be severe. For most people, the first sign is difficulty walking and balancing, which gets worse as time progresses. The symptoms usually start in a person's forties or fifties but can begin as early as the late teens. There is no known cure. And, until now, there was no known cause. Now, after 25 years of uncertainty, a multinational study led by Stefan Pulst, M.D., Dr. med., professor and chair of neurology, and K. Pattie Figueroa, a project manager in neurology, both in the Spencer Fox Eccles School of Medicine at University of Utah, has conclusively identified the genetic difference that causes SCA4, bringing answers to families and opening the door to future treatments. Their results are published in the peer-reviewed journal Nature Genetics. Solving a genetic enigma SCA4's pattern of inheritance had long made it clear that the disease was genetic, and previous research had located the gene responsible to a specific region of one chromosome. But that region proved extraordinarily difficult for researchers to analyze: full of repeated segments that look like parts of other chromosomes, and with an unusual chemical makeup that makes most genetic tests fail. To pinpoint the change that causes SCA4, Figueroa and Pulst, along with the rest of the research team, used a recently developed advanced sequencing technology. By comparing DNA from affected and unaffected people from several Utah families, they found that in SCA4 patients, a section in a gene called ZFHX3 is much longer than it should be, containing an extra-long string of repetitive DNA. Isolated human cells that have the extra-long version of ZFHX3 show signs of being sick -- they don't seem able to recycle proteins as well as they should, and some of them contain clumps of stuck-together protein. "This mutation is a toxic expanded repeat and we think that it actually jams up how a cell deals with unfolded or misfolded proteins," says Pulst, the last author on the study. Healthy cells need to constantly break down non-functional proteins. Using cells from SCA4 patients, the group showed that the SCA4-causing mutation gums up the works of cells' protein-recycling machinery in a way that could poison nerve cells. Hope for the future Intriguingly, something similar seems to be happening in another form of ataxia, SCA2, which also interferes with protein recycling. The researchers are currently testing a potential therapy for SCA2 in clinical trials, and the similarities between the two conditions raise the possibility that the treatment might benefit patients with SCA4 as well. Finding the genetic change that leads to SCA4 is essential to develop better treatments, Pulst says. "The only step to really improve the life of patients with inherited disease is to find out what the primary cause is. We now can attack the effects of this mutation potentially at multiple levels." But while treatments will take a long time to develop, simply knowing the cause of the disease can be incredibly valuable for families affected by SCA4, says Figueroa, the first author on the study. People in affected families can learn whether they have the disease-causing genetic change or not, which can help inform life decisions such as family planning. "They can come and get tested and they can have an answer, for better or for worse," Figueroa says. The researchers emphasize that their discoveries would not have been possible without the generosity of SCA4 patients and their families, whose sharing of family records and biological samples allowed them to compare the DNA of affected and unaffected individuals. "Different branches of the family opened up not just their homes but their history to us," Figueroa says. Family records were complete enough that the researchers were able to trace the origins of the disease in Utah back through history to a pioneer couple who moved to Salt Lake Valley in the 1840s. Since meeting so many families with the disease, studying SCA4 has become a personal quest, Figueroa adds. "I've been working on SCA4 directly since 2010 when the first family approached me, and once you go to their homes and get to know them, they're no longer the number on the DNA vial. These are people you see every day… You can't walk away. This is not just science. This is somebody's life." This work was performed in collaboration with researchers from University of Tübingen, University of Lübeck and Kiel University, University Hospital Hamburg-Eppendorf, and Veterans Administration Medical Center, Albany, NY. The study was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number R35127253 and the DFG-funded INST 37/1049-1.

As the population ages, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's are surging, presenting significant threats to public health and weighing on society. However, effective treatments for most neurodegenerative conditions remain elusive, with existing options merely providing symptomatic relief without targeting the root causes. While some biologic therapies have shown early promise in treating these diseases, developing small molecule drugs that are affordable and convenient continues to pose a major challenge.  The  ”undruggable” targets of neurodegenerative diseasesThe “undruggables”A key reason for this difficulty lies in the "undruggable" nature of proteins involved in neurodegeneration.  Unlike traditional drug targets that have enzymatic activity and binding sites for small molecules to modulate their functions, pathological proteins in neurodegenerative diseases are often misfolded, lacking sites that drugs could target, making medication development extremely hard. Despite decades of efforts, successes in developing effective neurodegenerative disease therapies like Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS) remain scarce. The intricate disease etiology, unique target traits, and inherent obstacles in delivering therapeutics to the nervous system pose formidable challenges for drug development.  However, evidence from human genetics and animal models implicates amyloid-β (Aβ) and tau in Alzheimer's disease, α-synuclein in Parkinson's disease, TDP-43 in amyotrophic lateral sclerosis and frontotemporal dementia, and mutant huntingtin (mHTT) in Huntington's disease as central to the pathological processes and progression of these conditions. Together, they represent potential drug targets that can be addressed through various strategies.    Synapse record shows 11 drugs targeting TDP-43 for ALS Broadly speaking, these strategies fall into indirect or direct targeting approaches, and each category can then be further divided based on the pathways involved. Indirect approaches aim to modulate factors that influence protein levels or aggregation, while direct approaches seek to target pathogenic proteins or their interactions directly. Different strategies for drugging the “undruggable” targetsIndirect Targeting StrategiesWhile directly targeting "misfolded" pathogenic proteins is difficult, modifying upstream or downstream factors may be more feasible. For instance, through omics screens, researchers identified the upstream genes v-ATPase and GPR52 that modulate levels of Ataxin 2 (implicated in ALS and SCA2) and mutant huntingtin (mHTT). Follow-up studies have demonstrated that the utilization of small molecules to inhibit v-ATPase and GPR52 can efficiently and securely decrease Ataxin 2 and mHTT expression in both mouse and human neurons, leading to a notable enhancement of disease phenotypes associated with the condition. This approach involves designing drugs that specifically target the more "druggable" upstream modifiers of pathogenic proteins. However, as these upstream genes serve normal functions, the inhibition or activation of them can potentially lead to side effects, thereby limiting the effectiveness of this strategy. It will be crucial to establish a therapeutic window that enables the reduction of disease proteins without interfering with the essential functions of the modifiers. Alternatively, targeting downstream molecular pathways can also offer opportunities. Misfolded proteins can elicit neurodegeneration through complex mechanisms. Researchers have discovered that the inhibition of the p53-Puma pathway, which is activated in both ALS and FTD, effectively prevented neuronal death in both cell and animal models. These findings suggest that Puma inhibitors may have therapeutic potential for the treatment of these disorders. Likewise, the inhibition ofRIPK1, a crucial mediator of cell death and inflammation pathways in neurodegenerative disorders, has demonstrated safety both in preclinical and clinical studies. This presents opportunities for the treatment of diseases such as Alzheimer's, ALS, and multiple sclerosis. Overall, these strategies aim to target the aberrantly activated pathways in neurodegeneration, potentially with fewer side effects. However, targeting individual downstream proteins may also have limitations, since misfolded proteins trigger related diseases through diverse signaling routes, potentially interfering with or compensating for drugs against these pathways. Direct Targeting StrategiesAlthough directly reducing misfolded protein levels with small molecules is unfeasible, targeted protein degradation technologies, such as PROTACs and AUTOTACs, provide viable alternatives. These technologies function similarly, comprising three components: a ligand that binds to the target protein, a ligand for cellular degradation machinery components, and a linker that connects them.  329 drugs fall under the PROTAC category in Synapse.By acting as "molecular bridges," they facilitate interactions between targets and degradation elements, leading to the breakdown of the target. However, PROTACs and AUTOTACs are large, chimeric molecules with suboptimal drug properties. As chimeras, they often exhibit poor blood-brain barrier penetration, which poses challenges for treating neurodegenerative diseases. Recently, researchers proposed a new autophagy-targeting "molecular glue" strategy called ATTEC (AuTophagy-TEthering Compounds), which effectively addresses these issues. Studies have demonstrated that these "molecular glues" can degrade mutant huntingtin without affecting normal huntingtin, thereby rescuing Huntington's disease phenotypes in cells, flies, and mice. With molecular weights ranging from 250-500 Da, some "molecular glues" can cross the blood-brain barrier, exhibiting enhanced drug-like properties and representing potent tools for neurodegenerative drug discovery.  The ”molecular glue”Furthermore, "molecular glues" have uses beyond protein degradation; they can also elevate protein levels. For disorders caused by haploinsufficiency, upregulating wild-type protein levels may be desirable. In such cases, "molecular glues" can bind wild-type proteins to prevent their degradation by deubiquitinases. Small molecule induced protein degradationUnlike directly targeting neurodegenerative proteins, another strategy uses small molecule drugs against their encoding RNAs.  For example, small molecules can alter mRNA splicing. Novartis reported an orally available small molecule, branaplam, that lowers mutant huntingtin levels by introducing a termination codon into mRNA via splicing modulation, decreasing mutant and normal HTT production. This compound was previously reported to increased SMN protein in spinal muscular atrophy (SMA) by stabilizing SMN2 gene products, and a similar drug from Roche was approved by FDA in 2021 for SMA.    In addition to the aforementioned strategies, Matthew Disney's team has developed RNase recruitment bivalent oligonucleotides (RIBOTACs) that offer new RNA degradation options. RIBOTACs interact with target RNAs to recruit RNase L for degradation, and preclinical studies have shown their effectiveness in degrading RNAs with expanded repeats, thereby alleviating ALS/FTD phenotypes. However, the recognition of specific RNAs by small molecules is limited to specialized structures, usually in GC-rich repetitive sequences, and RIBOTACs are relatively large and unable to penetrate the brain effectively. Nonetheless, these results pave the way for future research directions. Aberrant organelles in neurodegeneration may also provide insights into drug development. Mitochondrial damage and lipid accumulation are prominent features, and while organelles have been difficult targets in the past, recent advancements have expanded degradation technologies to include organelles. Methods to degrade mitochondria (AUTAC4) and lipid droplets (LD·ATTEC) have been developed, but further studies are necessary to determine if these compounds can ameliorate disease phenotypes. Although developing small molecule drugs for neurodegenerative diseases is crucial, it has been challenging to target "undruggable" proteins. However, recent technological advancements have provided potential strategies for engaging with these difficult targets, offering hope for patients. Should these strategies prove successful, they could lead to transformative breakthroughs in neurodegenerative drug discovery and inform the targeting of "undruggable" proteins in other diseases as well. Reference Junmei Lu, Zhaoyang Li, Aaron D. Gitler, Boxun Lu. Drugging “undruggable” neurodegenerative disease targets with small molecules. Science Bulletin 2023.

Researchers from the Cleveland Clinic have uncovered a greater understanding of the underlying causative mechanisms responsible for cognitive impairment in patients with coronavirus disease 2019 (COVID-19), providing greater insight into an issue that has remained largely shrouded in uncertainty over the past year. The study, published online in Alzheimer’s Research & Therapy, used artificial intelligence to compare datasets comprising patients with COVID-19 and Alzheimer's disease (AD). The investigators reported no evidence suggesting SARS-CoV-2 directly infects the brain; however, there was evidence of network-based associations between the novel coronavirus and genes and proteins associated with AD and other neurologic conditions. Additionally, the investigators assessed possible relationships between COVID-19 and neuroinflammation and brain microvascular injury – two hallmarks of AD. Significant associations were found between both pathways implicated in dementia. Also, the investigators detected abnormal AD biomarker expression in cerebrospinal fluid and blood of patients who had COVID-19. Elevated expression of BSG and FURIN, two SARS-CoV-2 host factors, as well as antiviral defense genes LY6E, IFITM2, IFITM3, and IFNAR1 were observed in the brain endothelial cells of patients with AD as well as healthy controls compared with neurons and other types of cells. The researchers wrote that this finding suggests brain microvascular injury plays a potential role in COVID-19-mediated cognitive impairment. In addition, patients with APOE E4/E4, the AD risk allele, demonstrated evidence of reduced antiviral defense gene expression compared with patients who carried APOE E3/E3, indicating “a lack of expression of these genes and potentially an elevated risk of SARS-CoV-2 infection” in these patients. "We discovered that SARS-CoV-2 infection significantly altered Alzheimer's markers implicated in brain inflammation and that certain viral entry factors are highly expressed in cells in the blood-brain barrier," according to a statement made by lead study author Feixiong Cheng, PhD, an assistant staff at Cleveland Clinic's Genomic Medicine Institute. "These findings indicate that the virus may impact several genes or pathways involved in neuroinflammation and brain microvascular injury, which could lead to Alzheimer's disease-like cognitive impairment." These new research findings immediately follow other recent studies in so-called COVID-19 “long haulers,” many of whom have frequently complained of “brain fog” and other cognitive issues. In one of those studies, published in The Lancet Psychiatry, researchers found that out of 236,379 patients who had recovered from COVID-19, approximately one out of three received a diagnosis for a neuropsychiatric condition within six months. Mood disorders were the most common diagnoses. Another study in the Annals of Clinical and Translational Neurology reported that 85% of non-hospitalized patients with long COVID-19 reported at least four long-term neurologic issues. Late last year, when the ongoing pandemic still gripped the world, researchers also found that COVID-19 could age the brain and lead to cognitive decline equivalent to the brain aging by up to 10 years. The study, which included 84,000 patients from London, suggested that the infection with the novel coronavirus was linked to significant cognitive deficits for months. It remains unclear whether these cognitive deficits are transient or permanent or if vaccines could offer hope for long-haul COVID-19. "Identifying how COVID-19 and neurological problems are linked will be critical for developing effective preventive and therapeutic strategies to address the surge in neurocognitive impairments that we expect to see in the future," added Dr. Cheng.