Focus on neurodegenerative diseases
Nature Neuroscience presents a collection of Reviews on recent advances in neurodegenerative disease, highlighting shared mechanisms across diseases and the gaps in our knowledge that still need to be addressed.
Neurodegenerative diseases cause progressive loss of brain functions associated with aging. Here we review intricate genotype–phenotype relationships, shared pathogenic mechanisms, and emerging therapeutic opportunities and challenges.
Older people often have more than one form of neuropathology. The authors describe how insights from the genomic architecture of syndromically defined neurodegenerative diseases can be integrated to inform person-specific trajectories of brain aging.
Adequate blood supply and vascular integrity are key to normal brain functioning. Cerebral blood flow and blood–brain barrier disruption contribute to Alzheimer’s disease and other neurodegenerative disorders as reviewed in humans and animal models.
A newly recognized process in neurodegenerative disease is accumulation of misfolded protein aggregates that self-replicate to spread damage between cells and tissues. This process has implications in designing strategies for treatment and diagnosis.
Many neurodegenerative diseases involve the seeded propagation and spread of abnormally shaped proteins within the nervous system. The resulting disease reflects the interaction between the misfolded proteins and the host milieu.
Neurodegenerative diseases impact specific cell populations within the brain. However, not all cells within the population are impacted, a phenomenon called selective cellular vulnerability. The molecular basis of this vulnerability is discussed.
Microglia are the sentinels, housekeepers, and defenders of the brain. In this review we consider the immune checkpoints that control microglial functions and discuss how their imbalance and subsequent neuroinflammation leads to neurodegeneration.
The authors review the current state of rodent models for AD, PD, FTD, and ALS. Limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders are discussed.
From the archive
Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies
Transposable elements, or ‘jumping genes’, constitute ~45% of the human genome. Sun et. al. report that jumping gene dysregulation is a pharmacologically targetable driver of cell death in neurodegenerative tauopathies, including Alzheimer’s disease.
A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease
This study describes a 3D human neuron-astrocyte-microglia triculture model of Alzheimer’s disease using a microfluidic platform and recapitulating plaque and tangle pathology, microglial recruitment, neuroinflammation, and cell death.
A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease
The authors constructed and validated a molecular network of the aging human cortex from RNA sequencing data from 478 individuals and identified genes that affect cognitive decline or neuropathology in Alzheimer’s disease.
TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD, leading to aberrant Mapt splicing and a paucity of parvalbumin interneurons. Phenotypic heterogeneity is exploited to yield modifiers of disease.
By comparing the genome-wide profile of H4K16ac in AD with younger and elder controls, the authors propose a mechanism for how age is a risk factor for AD: a histone modification, whose accumulation is associated with aging, is dysregulated in AD.
Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy
Using an inducible mouse model of sporadic ALS, Spiller et al. show that spinal microgliosis is not a major feature of TDP-43-triggered disease. Instead, microglia mediate TDP-43 clearance and motor recovery, suggesting a neuroprotective role in ALS.
The key driver of early-stage Alzheimer’s pathophysiology remains controversial. Styr and Slutsky propose that failures in firing homeostasis and imbalance between stability and plasticity represent the driving force of early disease progression.
Structural tract alterations predict downstream tau accumulation in amyloid-positive older individuals
Using longitudinal multimodal imaging data collected in healthy older individuals, Jacobs et al. provide in vivo evidence in humans that amyloid deposition facilitates tau spread along connected pathways and memory decline.
Striatal neurons directly converted from Huntington’s disease patient fibroblasts recapitulate age-associated disease phenotypes
Direct neuronal conversion of skin fibroblasts from individuals with Huntington’s disease (HD) generates a population of medium spiny neurons that recapitulate hallmarks of HD, including aggregation of mutant huntingtin protein, DNA damage and spontaneous cell death.
Pathological TDP-43 protein aggregates are a hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 pathology alters the morphology of nuclear pore complexes and cause deficits in nucleocytoplasmic transport.
Apicco and colleagues show that reducing TIA1 inhibits tau-mediated neurodegeneration and improves survival in a mouse model of tauopathy. This rescue occurs with a transition in tau aggregation from oligomeric to fibrillar forms of tau. These findings suggest a key role for RNA binding proteins in the pathophysiology of tau.
The precise underpinnings of Parkinson's disease and other disorders associated with the accumulation of α-synuclein are unclear. This study shows that PrPC mediates α-synuclein-associated synaptic dysfunction and memory deficits. Blocking specific events in receptor biology rescued cognitive deficits in mice, suggesting new possibilities for intervention in synucleinopathies.
Dopamine has long been thought to contribute to neurodegeneration in Parkinson's disease. The authors show that dopamine-induced neuron death in the substantia nigra is dependent on α-synuclein and coincides with increased levels of α-synuclein oligomers. The results suggest a synergistic interaction between dopamine and α-synuclein that underlies neuronal vulnerability in disease.
Neocortical resident microglia are long-lived cells. Füger et al. report that approximately half of these cells survive for the entire lifespan of a mouse. While microglial proliferation under homeostatic conditions is low, proliferation is increased in a mouse model of Alzheimer's disease.
The mechanisms underpinning neuronal death in Alzheimer's disease (AD) remain unclear. Caccamo and colleagues show that necroptosis contributes to neurodegeneration in AD. Blocking necroptosis reduced neuronal loss in a mouse model of AD, suggesting that necroptosis might be a therapeutic target in AD.
An expanded repetition of a DNA sequence within the C9orf72 gene is the most common genetic cause for motor neuron disease and frontotemporal dementia. In this study, the authors show that this expansion causes increased genomic breaks and reduces the cell's ability to repair the breaks, ultimately leading to neuronal cell death.
The authors identified a protective genetic allele associated with lower PU.1 (SPI1) expression in myeloid cells by conducting a genome-wide scan of Alzheimer's disease (AD). PU.1 binds the promoters of AD-associated genes (e.g., CD33, MS4A4A & MS4A6A, TYROBP) and modulates their expression, suggesting it may reduce AD risk by regulating myeloid cell gene expression.
Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy
The authors show that in a mouse model of spinal muscular atrophy (SMA), there is a reduction in sensory synaptic drive that leads to motor neuron dysfunction and motor behavior impairments. SMA motor neurons showed a lower surface expression of Kv2.1 potassium channels and reduced spiking ability. Increasing neuronal activity pharmacologically led to the normalization of Kv2.1 surface expression and an improvement in motor function.
Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
The Huntington's disease (HD) induced pluripotent stem cell (iPSC) consortium describe the combined use of differentiated patient-derived iPSCs and systems biology to discover underlying mechanisms in HD. They identify neurodevelopmental deficits in HD cells that can be corrected in cells and in vivo with a small molecule.
The authors used knockout mice to demonstrate the normal function of the protein α-synuclein, which has a central role in Parkinson's and other neurodegenerative diseases. The presynaptic protein promoted dilation of the exocytotic fusion pore, and mutations that cause Parkinson's disease specifically impaired this normal function.
Nusinersen (Spinraza) is a recently approved drug for treating spinal muscular atrophy. Approval of nusinersen may signal new opportunities for using antisense oligonucleotides as treatments for devastating neurological diseases.
The authors show that tau can be released by neurons and transferred to other neurons via the extracellular space. Moreover, they show that enhancing neuronal activity accelerates transneuronal tau propagation and exacerbates tau pathology.
In this Review, a collaboration of leading experts in amyotrophic lateral sclerosis (ALS) research present the state of the field regarding the use patient-derived induced pluripotent stem cells to generate motor neurons in vitro. Motor neuron characterization, including transcriptomics, molecular markers, neuron function and electrophysiology, are discussed in the context of maturation and disease.
In this Perspective the authors provide a comparison of recent neurophysiological findings on the pathophysiology of three major movement disorders: Huntington's disease, l-DOPA-induced dyskinesia and dystonia. Both clinical and preclinical studies show that these hyperkinetic disorders share mechanisms underlying synaptic scaling and synaptic plasticity alterations in the basal ganglia–thalamo-cortical network.
Zhang et al. show that the poly(GA) proteins produced in patients with C9ORF72 repeat expansions cause neurodegeneration and behavioral abnormalities when expressed in mice. The emergence of these phenotypes requires poly(GA) aggregation, and poly(GA) inclusions sequester HR23 proteins involved in proteasomal degradation, as well as proteins involved in nucleocytoplasmic transport.