D1 receptors and HD

HD Lighthouse Contributing Editor's Comment: This study adds to our basic knowledge about Huntington's Disease but its impact has been overstated with media headlines such as "Huntington's Disease may now be cured." As far as the HD community is concerned, HD may be cured at any time - we're waiting!

The researchers generated a mouse which progressively loses Dopamine 1 receptor cells. The mice display quite a number of Huntington's Disease like symptoms, including problems with swallowing. The focus in Huntington's disease has been on problems with the dopamine 2 receptor cells but this study suggests that a closer look should be taken at the role of dopamine 1 receptor cells in the disease.

The researchers conclude that "The therapeutic implication of this study is that cell replacement and symptomatic drug strategies would need to target the D1 receptor subpopulation to reverse some aspects of HD disability."

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 19 May 2007

"It was the lack of effective treatments for patients that inspired me to undertake this research, so it is extremely satisfying to solve another piece of the Huntington's disease puzzle and work towards a cure for this progressive genetic disease" - John Drago, principal research fellow, Howard Florey Institute

Researchers at Melbourne’s Howard Florey Institute have opened up new treatment possibilities for Huntington’s disease by proving a scientific theory incorrect.

It was previously thought that dopamine neurons, called D2 neurons, were responsible for the devastating symptoms seen in Huntington’s disease but the Florey researchers have proven that loss of D1 neurons causes many of the fatal diseases disabling symptoms.

In Huntington’s disease, the first evidence of damage in the brain occurs in the part of the brain called the striatum; D1 and D2 neurons constitute 90% of neurons in the striatum.

Research leader, Assistant Professor John Drago, said now that the importance of D1 neurons in HD had been established, they could work towards therapies that focused on both D1 and D2 neurons.

“Currently there is no effective treatment for Huntington’s disease and patients suffer from debilitating movement, memory, and psychiatric problems,” he said.

Dr. Drago’s discovery was made after he genetically engineered a mouse that displayed Huntington’s disease features by damaging only D1 neurons.

While a mouse model that carries the human Huntington's disease gene already exists, Dr. Drago’s mouse model is the first in the world to accurately mimic the death of the D1 neurons in the striatum.

“Despite the widespread death of D1 neurons, the mouse was healthy, apart from having HD symptoms,” Dr. Drago said.

“This indicates that there is potential for a tremendous amount of natural repair occurring in the Huntington’s diseased brain.”

“Now the challenge is to thoroughly understand how this natural repair occurs so we can develop a therapy that encourages and enhances repair in human patients.”

“Using the brain’s own adult stem cells to naturally repair and prevent further damage is one treatment possibility that we eventually hope to explore,” he said.

In addition to his research career, Assistant Dr. Drago is a neurologist at the St Vincent’s Hospital Movement Disorder Clinic, where he treats patients with HD.

“It was the lack of effective treatments for patients that inspired me to undertake this research, so it is extremely satisfying to solve another piece of the Huntington’s disease puzzle and work towards a cure for this progressive genetic disease,” he said.

A/Prof Drago’s research was published in the 26 February 2007 edition of the highly prestigious Proceedings of the National Academy of Sciences journal.

He was assisted by Dr Ilse Gantois, a postdoctoral researcher from Belgium, and the Florey’s Neuroimaging group led by A/Prof Gary Egan, who undertook MRI scans of the mouse model to show its shrinking striatum as D1 neurons were dying and the response of the brain by making glial cells.

The Florey is taking two different approaches to its Huntington's disease research with this investigation and also Dr Anthony Hannan's environmental enrichment research, which has shown that physical and mental stimulation, can delay the onset of the disease and slow the progression of symptoms.

By tackling HD from two different angles, the Florey researchers hope to accelerate their discoveries into clinical outcomes to benefit HD patients.

The Abstract

Huntington's disease is characterized by death of striatal projection neurons. We used a Cre/Lox transgenic approach to generate an animal model in which D1 dopamine receptor (Drd1a)+ cells are progressively ablated in the postnatal brain. Striatal Drd1a, substance P, and dynorphin expression is progressively lost, whereas D2 dopamine receptor (Drd2) and enkephalin expression is up-regulated. Magnetic resonance spectroscopic analysis demonstrated early elevation of the striatal choline/creatine ratio, a finding associated with extensive reactive striatal astrogliosis. Sequential MRI demonstrated a progressive reduction in striatal volume and secondary ventricular enlargement confirmed to be due to loss of striatal cells. Mutant mice had normal gait and rotarod performance but displayed hindlimb dystonia, locomotor hyperactivity, and handling-induced electrographically verified spontaneous seizures. Ethological assessment identified an increase in rearing and impairments in the oral behaviors of sifting and chewing. In line with the limbic seizure profile, cell loss, astrogliosis, microgliosis, and down-regulated dynorphin expression were seen in the hippocampal dentate gyrus. This study specifically implicates Drd1a+ cell loss with tail suspension hindlimb dystonia, hyperactivity, and abnormal oral function. The latter may relate to the speech and swallowing disturbances and the classic sign of tongue-protrusion motor impersistence observed in Huntington's disease. In addition, the findings of this study support the notion that Drd1a and Drd2 are segregated on striatal projection neurons.

Source: Proceedings of the Nat'l Academy of Sciences of the USA. March 6, 2007 vol. 104, pp. 4182-4187

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