Niemann Pick diseases are a group of rare genetic diseases related to the accumulation of lipids or fats in lysosomes, cellular organelles that act as recycling centers, digesting complex molecules and discarding unwanted material. Specifically, Niemann-Pick disease type C is caused by mutations in the lysosomal protein that transports cholesterol, called NPC1. The disease is inherited in an autosomal recessive manner, so that both the father and the mother carry a mutated copy of the gene, and causes the accumulation of cholesterol in the lysosomes, leading mainly to neurological problems.

The symptoms of this disorder vary depending on the age of onset (childhood, youth or adult) and include motor and cognitive problems, ataxia, seizures and psychiatric disorders that can lead to psychosis and dementia. Psychiatric disorders are related to problems in the connections between neurons, or synapses, since these control both cognition (memory, learning, etc.) as well as emotions and behavior. The molecular mechanisms that cause these symptoms are not known, although it has been shown that the NPC1 protein can influence memory processes and synaptic plasticity.

A new investigation, led by the Severo Ochoa Molecular Biology Center (CBM), a joint center of the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid (UAM), has focused on studying Niemann-Pick type disease. c.

The research results demonstrate the role of a receptor in the increase in neuronal cholesterol, which contributes to understanding the psychiatric disorder associated with the disease and opens new therapeutic perspectives for its treatment.

The research team, headed by Ana Toledano-Zaragoza, from the CBM, has thoroughly examined the metabotropic glutamate receptor, a protein that also participates in synaptic plasticity events and whose alterations have been associated with different psychiatric pathologies.

“The cellular distribution of this receptor is key for its correct functioning,” says María Dolores Ledesma, also a CBM scientist and co-author of the research. “It can be located both inside cells and in their plasma membrane, where it binds to regions enriched in cholesterol, which suggests that the amount of this lipid may be important for its function,” he adds.

The research team observed that, in neurons deficient in NPC1, excess cholesterol traps the receptor in lysosomes, therefore reducing its levels in the plasma membrane. “We have seen that the receptor is functional when it is in the lysosomes, so its accumulation leads to aberrant overactivation,” says Violeta Enríquez Zarralanga, CBM researcher and also co-author of the study.

Mouse neurons model for Niemann Pick type C disease stained for the total metabotropic receptor in green or surface in red. (Photo: Ana Toledano-Zaragoza)

The results indicate that oral treatment with the drug CTEP, which blocks the metabotropic glutamate receptor, reduces its activity in lysosomes and reduces psychiatric alterations in model mice for Niemann Pick disease type C.

The work also shows the accumulation of the receptor in neurons of patients with the disease, so these results provide a new treatment strategy for the psychiatric symptoms they present.

The study is titled “Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease.” And it has been published in the academic journal Cell Death & Disease. (Source: CBM / CSIC / UAM)

Niemann Pick diseases are a group of rare genetic diseases related to the accumulation of lipids or fats in lysosomes, cellular organelles that act as recycling centers, digesting complex molecules and discarding unwanted material. Specifically, Niemann-Pick disease type C is caused by mutations in the lysosomal protein that transports cholesterol, called NPC1. The disease is inherited in an autosomal recessive manner, so that both the father and the mother carry a mutated copy of the gene, and causes the accumulation of cholesterol in the lysosomes, leading mainly to neurological problems.

The symptoms of this disorder vary depending on the age of onset (childhood, youth or adult) and include motor and cognitive problems, ataxia, seizures and psychiatric disorders that can lead to psychosis and dementia. Psychiatric disorders are related to problems in the connections between neurons, or synapses, since these control both cognition (memory, learning, etc.) as well as emotions and behavior. The molecular mechanisms that cause these symptoms are not known, although it has been shown that the NPC1 protein can influence memory processes and synaptic plasticity.

A new investigation, led by the Severo Ochoa Molecular Biology Center (CBM), a joint center of the Higher Council for Scientific Research (CSIC) and the Autonomous University of Madrid (UAM), has focused on studying Niemann-Pick type disease. c.

The research results demonstrate the role of a receptor in the increase in neuronal cholesterol, which contributes to understanding the psychiatric disorder associated with the disease and opens new therapeutic perspectives for its treatment.

The research team, headed by Ana Toledano-Zaragoza, from the CBM, has thoroughly examined the metabotropic glutamate receptor, a protein that also participates in synaptic plasticity events and whose alterations have been associated with different psychiatric pathologies.

“The cellular distribution of this receptor is key for its correct functioning,” says María Dolores Ledesma, also a CBM scientist and co-author of the research. “It can be located both inside cells and in their plasma membrane, where it binds to regions enriched in cholesterol, which suggests that the amount of this lipid may be important for its function,” he adds.

The research team observed that, in neurons deficient in NPC1, excess cholesterol traps the receptor in lysosomes, therefore reducing its levels in the plasma membrane. “We have seen that the receptor is functional when it is in the lysosomes, so its accumulation leads to aberrant overactivation,” says Violeta Enríquez Zarralanga, CBM researcher and also co-author of the study.

Mouse neurons model for Niemann Pick type C disease stained for the total metabotropic receptor in green or surface in red. (Photo: Ana Toledano-Zaragoza)

The results indicate that oral treatment with the drug CTEP, which blocks the metabotropic glutamate receptor, reduces its activity in lysosomes and reduces psychiatric alterations in model mice for Niemann Pick disease type C.

The work also shows the accumulation of the receptor in neurons of patients with the disease, so these results provide a new treatment strategy for the psychiatric symptoms they present.

The study is titled “Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease.” And it has been published in the academic journal Cell Death & Disease. (Source: CBM / CSIC / UAM)