New insight into dementia pathophysiology

November 17, 2010

New research unravels a key molecular pathway underlying a neurodegenerative disorder that causes a devastating type of dementia. The study, published by Cell Press in the November 18 issue of the journal Neuron, sheds light on the pathological processing of Progranulin, a protein that normally promotes the survival of brain cells but is reduced in some neurodegenerative diseases.

Frontotemporal lobar degeneration (FTLD) refers to a group of disorders associated with degeneration of the frontal and temporal lobes of the brain. Symptoms include , aphasia, and semantic disorders. Mutation of the gene for PGRN is associated with the most common form of FTLD, which is also characterized by inclusions of TDP-43 protein in the brain. Abnormal accumulation of TDP-43 has also been linked with amyotrophic (ALS).

While it is clear that a reduction in PGRN is causative for FTLD-TDP, the underlying mechanism is unknown. "Elucidation of PGRN action and the control of PGRN levels may have broad relevance for both FTLD and ALS," explains senior study author, Dr. Stephen M. Strittmatter from Yale University School of Medicine. "In order to advance the understanding of PGRN biology, we searched for cell surface binding sites that interact with PGRN."

Dr. Strittmatter and colleagues identified Sortilin as a key PGRN binding site on the surface of cortical neurons. In the stressed nervous system, PGRN was not expressed in neurons, but in nearby glial cells. Sortilin rapidly transferred PGRN inside of the neurons and delivered it to lysosomes, cellular structures that degrade proteins. Mice that did not express Sortilin exhibited high levels of extracellular PGRN. Importantly, mice with a PGRN deficiency similar to that seen in FLTD-TDP, were fully normalized with regards to PGRN levels when Sortilin was deleted.

Taken together, the findings implicate Sortilin-mediated PGRN endocytosis in FTLD-TDP pathophysiology and identify Sortilin binding as a potential therapeutic site to alter PGRN pathology. However, the authors are careful to caution that additional studies elucidating the connection between PGRN, Sortilin, and TDP-43 are needed. "Future functional studies of Sortilin in PGRN biology will require development of robust rodent models for PGRN-dependent neurodegeneration," says Dr. Strittmatter. "Nevertheless, our work implicates Sortilin-mediated PGRN endocytosis as a key pathway for further study in FTLD, and possible ALS, pathophysiology."

Related Stories

Recommended for you

Scientists reveal new avenue for drug treatment in neuropathic pain

November 24, 2017
New research from King's College London has revealed a previously undiscovered mechanism of cellular communication, between neurons and immune cells, in neuropathic pain.

Small but distinct differences among species mark evolution of human brain

November 23, 2017
The most dramatic divergence between humans and other primates can be found in the brain, the primary organ that gives our species its identity.

What if consciousness is not what drives the human mind?

November 22, 2017
Everyone knows what it feels like to have consciousness: it's that self-evident sense of personal awareness, which gives us a feeling of ownership and control over the thoughts, emotions and experiences that we have every ...

Team constructs whole-brain map of electrical connections key to forming memories

November 22, 2017
A team of neuroscientists at the University of Pennsylvania has constructed the first whole-brain map of electrical connectivity in the brain based on data from nearly 300 neurosurgical patients with electrodes implanted ...

To forget or to remember? Memory depends on subtle brain signals, scientists find

November 22, 2017
The fragrance of hot pumpkin pie can bring back pleasant memories of holidays past, while the scent of an antiseptic hospital room may cause a shudder. The power of odors to activate memories both pleasing and aversive exists ...

Pitch imperfect? How the brain decodes pitch may improve cochlear implants

November 22, 2017
Picture yourself with a friend in a crowded restaurant. The din of other diners, the clattering of dishes, the muffled notes of background music, the voice of your friend, not to mention your own – all compete for your ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.