Muscleblind proteins guarding the brain from toxic RAN proteins in myotonic dystrophy

Unlocking the Mystery of Myotonic Dystrophy Type 2: How Muscleblind Proteins Hold the Key to New Treatments

Avery Sinclair in Health & Wellness June 2025 • 4 min read.

"Groundbreaking research reveals the role of muscleblind proteins in regulating RAN translation in Myotonic Dystrophy Type 2, offering hope for targeted therapies."

Myotonic dystrophy (DM), a prevalent form of muscular dystrophy, manifests in two primary types: DM1 and DM2. While DM1 arises from a CTG expansion in the 3' UTR of the DMPK gene, DM2 is triggered by an intronic CCTG expansion in the CNBP gene. Although the genetic roots differ, both conditions share striking similarities in their impact on multiple organ systems, including skeletal muscle, heart, eyes, and endocrine functions. Notably, the central nervous system (CNS) involvement significantly affects patients' quality of life.

Recent research has shifted focus toward understanding how these genetic mutations express themselves beyond simple coding errors. The discovery of repeat-associated non-ATG (RAN) translation has opened new avenues for exploring the molecular mechanisms underlying these diseases. RAN translation allows the production of proteins from unconventional start sites within the repetitive sequences of the mutated genes, potentially leading to the accumulation of toxic proteins within cells.

A groundbreaking study led by researchers Tao Zu, John D. Cleary, and Laura P.W. Ranum, sheds light on the role of muscleblind proteins in regulating RAN translation in DM2. This study offers fresh insights into the disease's pathology and identifies new therapeutic targets for managing its effects on the brain and body.

What are RAN Proteins and Their Role in Myotonic Dystrophy Type 2?

Muscleblind proteins guarding the brain from toxic RAN proteins in myotonic dystrophy

The study reveals that the DM2 CCTG-CAGG expansion mutation leads to the production of RAN proteins through bidirectional transcription. This means that both the sense and antisense strands of the mutated gene are translated, resulting in the creation of unique tetrapeptide repeat proteins: poly-(LPAC) from the sense strand and poly-(QAGR) from the antisense strand.

Researchers found that these RAN proteins accumulate in distinct regions of the brain in DM2 patients. LPAC proteins were predominantly found in the gray matter regions, including neurons, astrocytes, and glia. Conversely, QAGR proteins were mainly located in the white matter, particularly within oligodendrocytes. This differential localization suggests that each RAN protein may contribute uniquely to the specific neurological symptoms observed in DM2.

Elevated CAGG Antisense Transcripts: DM2 autopsy brains show an increase in DM2-expanded CAGG antisense transcripts.
RAN Protein Expression: Poly-(LPAC) and poly-(QAGR) tetrapeptide RAN proteins are expressed in DM2-affected tissues.
MBNL Modulation: RAN translation in DM2 is modulated by MBNL levels through nuclear sequestration.
Nuclear Sequestration Failure: Failure of CCUG repeats to be properly sequestered in the nucleus leads to increased levels of RAN proteins.

To investigate the toxicity of LPAC and QAGR proteins, the researchers conducted cell-based assays. Results indicated that both LPAC and QAGR proteins are toxic to cells, independent of RNA gain-of-function effects. The arginine-containing dipeptides, QAGR, exhibited greater toxicity, aligning with previous findings on arginine-rich proteins.

Implications for Future Treatments

The discovery that muscleblind proteins modulate RAN translation opens possibilities for therapeutic interventions. The proposed two-phase model—involving initial nuclear retention of expansion RNAs followed by cytoplasmic RAN translation—suggests that targeting either phase could alleviate the disease's progression. Enhancing nuclear sequestration or inhibiting RAN translation might reduce the accumulation of toxic proteins and mitigate the symptoms of DM2.

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This article is based on research published under:

DOI-LINK: 10.1016/j.neuron.2017.08.039, Alternate LINK

Title: Ran Translation Regulated By Muscleblind Proteins In Myotonic Dystrophy Type 2

Subject: General Neuroscience

Journal: Neuron

Publisher: Elsevier BV

Authors: Tao Zu, John D. Cleary, Yuanjing Liu, Monica Bañez-Coronel, Jodi L. Bubenik, Fatma Ayhan, Tetsuo Ashizawa, Guangbin Xia, H. Brent Clark, Anthony T. Yachnis, Maurice S. Swanson, Laura P.W. Ranum

Published: 2017-09-01

Everything You Need To Know

What is Myotonic Dystrophy Type 2 and how does it differ from Type 1?

Myotonic Dystrophy (DM) is a form of muscular dystrophy that has two primary types: DM1 and DM2. DM1 is caused by a CTG expansion in the 3' UTR of the DMPK gene, whereas DM2 is caused by an intronic CCTG expansion in the CNBP gene. While they have different genetic causes, they both impact multiple organ systems including the skeletal muscle, heart, eyes, endocrine functions, and the central nervous system, affecting a patient's quality of life. The recent focus has been on understanding how these genetic mutations express themselves, leading to the discovery of RAN translation.

What are muscleblind proteins and what role do they play in Myotonic Dystrophy Type 2?

Muscleblind proteins (MBNL) modulate RAN translation in DM2 through nuclear sequestration. The failure of CCUG repeats to be properly sequestered in the nucleus leads to increased levels of RAN proteins. The study by researchers Tao Zu, John D. Cleary, and Laura P.W. Ranum, sheds light on the role of these proteins in regulating RAN translation in DM2, offering insights into the pathology and identifying new therapeutic targets for managing its effects on the brain and body.

What is RAN translation and how does it contribute to the development of Myotonic Dystrophy Type 2?

RAN translation, or repeat-associated non-ATG translation, is a process where proteins are produced from unconventional start sites within the repetitive sequences of mutated genes. In Myotonic Dystrophy Type 2, the CCTG-CAGG expansion mutation leads to the production of RAN proteins through bidirectional transcription. This results in the creation of unique tetrapeptide repeat proteins: poly-(LPAC) from the sense strand and poly-(QAGR) from the antisense strand. These RAN proteins accumulate in different brain regions and are toxic to cells, contributing to the disease's pathology.

Where do LPAC and QAGR proteins accumulate in the brain of patients with Myotonic Dystrophy Type 2, and what implications does this localization have?

In Myotonic Dystrophy Type 2 patients, LPAC proteins are predominantly found in the gray matter regions of the brain, including neurons, astrocytes, and glia. Conversely, QAGR proteins are mainly located in the white matter, particularly within oligodendrocytes. This differential localization indicates that each RAN protein may uniquely contribute to the specific neurological symptoms observed in DM2, potentially affecting different cell types and brain functions.

How might the understanding of muscleblind proteins and RAN translation in Myotonic Dystrophy Type 2 lead to new treatments?

The discovery that muscleblind proteins modulate RAN translation opens possibilities for therapeutic interventions in Myotonic Dystrophy Type 2. The proposed two-phase model suggests that targeting either the initial nuclear retention of expansion RNAs or inhibiting cytoplasmic RAN translation could alleviate the disease's progression. Enhancing nuclear sequestration or inhibiting RAN translation might reduce the accumulation of toxic proteins, mitigating the symptoms of DM2.