Tag: Neuroscience

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Cell stress-related biochemical events may be partly driving Parkinson’s disease

Cell stress-related biochemical events may be partly driving Parkinson's disease

Parkinson’s disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain, according to a new study from scientists at Scripps Research.

The discovery, published in The Journal of Neuroscience in February 2022, offers a clear and testable hypothesis about the progression of Parkinson’s disease, and may lead to treatments capable of significantly slowing or even stopping it.

We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the process of disease spread in the brain.”


Stuart Lipton, MD, PhD, study senior author, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department of Molecular Medicine at Scripps Research

Parkinson’s disease affects roughly one million people in the United States. Its precise trigger is unknown, but it entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson’s. A closely related syndrome in which dementia occurs early in the disease course is called Lewy Body Dementia (LBD), and affects about 1.4 million people in the U.S.

In both diseases, affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson’s and LBD, apparently transmitting the disease process through the brain. But precisely how alpha-synuclein aggregates build up and spread in this way has been unclear.

One clue, uncovered by Lipton’s lab and others in prior research, is that the Parkinson’s/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems, including “housekeeping” systems that normally keep protein aggregates under control.

In the new study, the Scripps Research team demonstrated the validity of this idea by showing that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.

The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson’s, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion of the aggregates by affected neurons, and some of these aggregates are taken up by nearby neurons.

“The process we observed seems very similar to what is seen in Parkinson’s and LBD brains,” says study first author Chang-Ki Oh, PhD, a staff scientist in the Lipton laboratory.

The researchers also tested postmortem brains of LBD patients, and again found that levels of S-nitrosylated p62 were abnormally high in affected brain areas-;supporting the idea that this process occurs in humans.

Lipton and Oh say that S-nitrosylation of proteins becomes more likely in many situations of cellular stress, including the presence of protein aggregates. Thus, this chemical modification of p62 could be a key factor in a self-reinforcing process that not only stresses brain cells beyond their limits, but also spreads the source of stress to other brain cells.

The team is now working to develop drug-like compounds that specifically inhibit the S-nitrosylation of p62. Although it would take years to develop such compounds as potential commercial drugs, they could, in principle, slow the Parkinson’s/LBD disease process or prevent its further spread in the brain after it begins, Lipton says.

Source:

Scripps Research Institute

Journal reference:

Oh, C., et al. (2022) S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson’s Disease and Lewy Body Dementia. Journal of Neuroscience. doi.org/10.1523/JNEUROSCI.1508-21.2022.

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Biological events occurring during puberty trigger sex differences in learning and memory

Biological events occurring during puberty trigger sex differences in learning and memory

New research from the University of California, Irvine reveals that sex differences in learning and memory mechanisms are triggered by biological events occurring during puberty. Findings show prepubescent female rodents have much better hippocampal long-term potentiation (LTP) and spatial learning than same-age males, but puberty has opposite consequences for synaptic plasticity in the two sexes.

The study, titled “Prepubescent female rodents have enhanced hippocampal LTP and learning relative to males, reversing in adulthood as inhibition increases” was recently published in Nature Neuroscience.

Since the late 19th century, the general consensus in the scientific community has been that men outperform women on spatial tasks, while women excel in learning tasks involving verbal material, while the general debate has been about why there is a difference.

The surprising conclusion from our results is that the polarization of sex differences in hippocampal synapses and related learning reverses in females and males from before to after puberty. This occurs because of distinct developmental changes. Thresholds for plasticity and encoding spatial information increase in females and decease in males.”


Christine Gall, PhD, co-corresponding author, and distinguished professor and chair of anatomy and neurobiology at the UCI School of Medicine

Puberty is a critical landmark in brain maturation and results in a wide variety of sex differences in behavior, but little is known about how it affects the substrates for memory encoding. Researchers identified a female-specific mechanism that increases the LTP threshold and decreases spatial memory from before to after puberty. Sex differences were demonstrated for hippocampus-dependent processes and driven by different underlying mechanisms.

In females only, inhibitory synapses in the CA1 field of the hippocampus exhibit an increase in levels of GABAA receptors containing the α5 subunit; this increase is associated with greater inhibition of synaptic activity critical for synaptic plasticity and memory. The α5 receptors have been linked to anxiety which also undergoes changes at the onset of the estrous cycle. Researchers found that pharmacological suppression of α5-GABAA receptors restored LTP and memory encoding in females to levels observed before puberty.

“Our team proposes that the emergent female pattern may favor learning in complex circumstances while the emergent male pattern favors rapid acquisition of simpler material. This idea suggests that optimal teaching strategies need to reflect previously unsuspected brain differences between the sexes and how these are dramatically adjusted during puberty,” Gall said. “The vast majority of studies have begun with analyses of young adult male rodents. Females use somewhat different memory mechanisms than do males and therefore may respond differently to drugs and gene mutations. This new research demonstrates the need for new sexually differentiated approaches for the development of therapeutic treatments and their applications at different life stages.”

Further research will be conducted to determine if the sex-specific LTP threshold changes identified in hippocampus during the transition to postpubertal life are evident in other brain areas and influence the encoding of different types of memories.

Source:

University of California, Irvine

Journal reference:

Le, A.A., et al. (2022) Prepubescent female rodents have enhanced hippocampal LTP and learning relative to males, reversing in adulthood as inhibition increases. Nature Neuroscience. doi.org/10.1038/s41593-021-01001-5.